Physiol Rev 86: 1151–1178, 2006;
doi:10.1152/physrev.00050.2005.
(Patho)physiological Significance of the Serum- and
Glucocorticoid-Inducible Kinase Isoforms
FLORIAN LANG, CHRISTOPH BÖHMER, MONICA PALMADA, GUISCARD SEEBOHM,
NATHALIE STRUTZ-SEEBOHM, AND VOLKER VALLON
Department of Physiology, University of Tuebingen, Tuebingen, Germany; and Departments of Medicine
and Pharmacology, University of California San Diego and San Diego Veterans Affairs
Healthcare System, San Diego, California
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I. Introduction
II. Regulation of Serum- and Glucocorticoid-Inducible Protein Kinases
A. Genomic control of SGK gene transcription
B. Regulation of SGK kinase activity
C. Degradation of SGKs
III. Role of Serum- and Glucocorticoid-Inducible Protein Kinases in the Regulation of Molecular
and Cellular Functions
A. Ion channels
B. Carriers and pumps
C. Enzyme activities
D. Transcription factors
E. Release of hormones
F. Regulation of cell volume
G. Cell proliferation and apoptosis
H. Other functions
IV. Role of Serum- and Glucocorticoid-Inducible Protein Kinases in the Regulation
of Integrated Functions
A. Metabolism
B. Kidney function and salt appetite
C. Gastrointestinal function
D. Other epithelia-containing tissues
E. Cardiovascular function
F. Neuromuscular function
G. Other functions
H. Phenotype of gene-targeted mice lacking SGK1, SGK3, or both
V. Pathophysiological Significance of the Serum- and Glucocorticoid-Inducible Protein Kinases
A. Tumor growth
B. Hypertension, obesity, and the metabolic syndrome
C. Neuronal disease
D. Diseases involving fibrosis
E. Ischemia
VI. Conclusions and Perspectives
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Lang, Florian, Christoph Böhmer, Monica Palmada, Guiscard Seebohm, Nathalie Strutz-Seebohm, and
Volker Vallon. (Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms.
Physiol Rev 86: 1151–1178, 2006; doi:10.1152/physrev.00050.2005.—The serum- and glucocorticoid-inducible kinase-1
(SGK1) is ubiquitously expressed and under genomic control by cell stress (including cell shrinkage) and hormones
(including gluco- and mineralocorticoids). Similar to its isoforms SGK2 and SGK3, SGK1 is activated by insulin and
growth factors via phosphatidylinositol 3-kinase and the 3-phosphoinositide-dependent kinase PDK1. SGKs activate
ion channels (e.g., ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g., NHE3, GLUT1, SGLT1,
EAAT1–5), and the Na⫹-K⫹-ATPase. They regulate the activity of enzymes (e.g., glycogen synthase kinase-3,
ubiquitin ligase Nedd4 –2, phosphomannose mutase-2) and transcription factors (e.g., forkhead transcription factor
FKHRL1, ␤-catenin, nuclear factor ␬B). SGKs participate in the regulation of transport, hormone release, neuroexcitability, cell proliferation, and apoptosis. SGK1 contributes to Na⫹ retention and K⫹ elimination of the kidney,
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mineralocorticoid stimulation of salt appetite, glucocorticoid stimulation of intestinal Na⫹/H⫹ exchanger and
nutrient transport, insulin-dependent salt sensitivity of blood pressure and salt sensitivity of peripheral glucose
uptake, memory consolidation, and cardiac repolarization. A common (⬃5% prevalence) SGK1 gene variant is
associated with increased blood pressure and body weight. SGK1 may thus contribute to metabolic syndrome. SGK1
may further participate in tumor growth, neurodegeneration, fibrosing disease, and the sequelae of ischemia. SGK3
is required for adequate hair growth and maintenance of intestinal nutrient transport and influences locomotive
behavior. In conclusion, the SGKs cover a wide variety of physiological functions and may play an active role in a
multitude of pathophysiological conditions. There is little doubt that further targets will be identified that are
modulated by the SGK isoforms and that further SGK-dependent in vivo physiological functions and pathophysiological conditions will be defined.
I. INTRODUCTION
Physiol Rev • VOL
II. REGULATION OF SERUM- AND
GLUCOCORTICOID-INDUCIBLE
PROTEIN KINASES
A. Genomic Control of SGK Gene Transcription
Transcription of SGK1 is upregulated by both serum
and glucocorticoids (49, 78, 96, 112, 162, 167, 221, 232,
289, 361, 362, 388). Several other hormones and mediators
stimulate SGK1 transcription, including mineralocorticoids (29, 49, 65, 96, 135, 168, 197, 206, 231, 290), gonad-
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The serum- and glucocorticoid-inducible kinase-1
(SGK1) was originally cloned as an immediate early gene
transcriptionally stimulated by serum and glucocorticoids
in rat mammary tumor cells (112, 361, 362). The human
isoform has been discovered as a cell volume-regulated
gene upregulated by cell shrinkage (349). As described in
more detail below, SGK1 is under transcriptional control
of numerous stimuli. Two closely related isoforms, referred to as SGK2 and SGK3, have subsequently been
identified that share 80% amino acid sequence identity in
their catalytic domain with SGK1 (172).
The gene encoding human SGK1 has been localized
to chromosome 6q23 (350), whereas the gene encoding
SGK2 is localized to chromosome 20q12 (182). SGK3 is
identical to the cytokine-independent survival kinase
CISK (203). The “SGK-like” gene (SGKL) in chromosome
8q12.3 (81) encodes a protein whose predicted amino acid
sequence is virtually identical to that of human SGK3.
SGK kinases are expressed in a wide variety of species including shark (348) and Caenorhabditis elegans
(142). Yeast express two orthologs, Ypk1 and Ypk2, which
are involved in endocytosis (87) and required for survival
(60). Yeast lacking Ypk1 and Ypk2 can be rescued by
mammalian SGK1 (60).
In mammals, SGK1 is expressed in virtually all tissues tested (349). However, transcript levels vary profoundly among different cell types of any given tissue,
such as brain (127, 236, 304, 318, 359), eye (260, 261, 283),
lung (360), kidney (65, 118, 147, 184, 206), liver (110),
intestine (352), pancreas (170), and ovary (7). Moreover,
typical expression patterns are found during embryonic
development (73, 152, 193). The subcellular localization of
SGK1 may depend on the functional state of the cell.
Activation of SGK1 after exposure of cells to serum has
been suggested to trigger importin-␣-mediated entry of
SGK1 into the nucleus (208), whereas activation by hyperosmotic shock or glucocorticoids enhances cytosolic
localization of the kinase (112).
SGK3 is expressed in all tissues tested thus far (172)
and is particularly high in the embryo (152, 193) and adult
heart and spleen (172). Expression of SGK2 is most abundant in epithelial tissues including kidney, liver, pancreas,
and presumably choroid plexus of the brain (172). The
subcellular distribution may be nuclear and cytoplasmic,
as SGK2 and SGK3 contain a similar nuclear localization
signal sequence as SGK1 (112).
The functional significance of SGK1, SGK2, and SGK3
is still far from understood. Notably, all three kinases are
potent regulators of ion channel activity, transport, and
transcription (30, 111, 183, 186, 250, 305, 331, 378). Functional analysis of gene-targeted mice lacking SGK1 (368)
and SGK3 (214) provided insight into the functional significance of SGK1- and SGK3-dependent regulation of
physiological functions. Interestingly, neither knockout of
SGK1 (368) or SGK3 (214), nor knockout of both SGK1
and SGK3 (133) leads to a severe phenotype, suggesting
that neither SGK1 nor SGK3 is required for survival.
Closer inspection of the physiology of those mice discloses, however, multiple physiological deficits pointing
to the broad functional role of these kinases.
The following review attempts to delineate the current knowledge on the physiological and pathophysiological significance of these interesting kinases. Our knowledge on each of the kinases is far from complete. Particularly our knowledge on the physiological significance of
SGK2 and SGK3 is presently, at best, fragmentary.
We first describe the mechanisms regulating expression, activity, and degradation of the SGKs (sect. II). Subsequently, we outline SGK-dependent regulation of molecular and cellular functions (sect. III). Where known,
consequences on integrated function are outlined (sect.
IV). Finally, we discuss the known and putative pathophysiological relevance of the SGKs (sect. V).
FUNCTIONAL SIGNIFICANCE OF SGK ISOFORMS
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tor, the activating protein 1 (AP1), the activating transcription factor 6 (ATF6), the heat shock factor (HSF),
reticuloendotheliosis viral oncogene homolog (c-Rel) and
nuclear factor ␬B (NF␬B), signal transducers and activators of transcription (STAT), the TGF-␤-dependent transcription factors SMAD3 and SMAD4, and forkhead activin signal transducer (FAST) (112).
The regulation of SGK1 transcript levels is fast; appearance and disappearance of SGK1 mRNA require ⬍20
min (349). Little is known about genomic regulation of
SGK2 and SGK3, which appear to be less sensitive to
hormonal regulation than SGK1 (182).
B. Regulation of SGK Kinase Activity
To become functional, the SGK protein kinases require activation by phosphorylation, which is accomplished through a signaling cascade involving PI 3-kinase,
the 3-phosphoinositide (PIP3)-dependent kinase PDK1,
and a yet unidentified but also PIP3-dependent kinase that
has been referred to as PDK2 or “hydrophobic motif”
(H-motif) kinase (5, 31, 75, 119, 171, 224, 235, 249, 369).
PIP3 is degraded by the phosphatase and tensin homolog
PTEN (202, 240, 309), which thus disrupts PI 3-kinasedependent activation of the SGKs.
Maximal stimulation of SGK1 activity requires the
PDK1-dependent phosphorylation at 256Thr within the activation loop (T-loop) and phosphorylation at 422Ser in the
hydrophobic motif at its COOH terminus by PDK2/H-motif
kinase (171, 172, 249). The PDK1-mediated SGK1 phosphorylation is facilitated when 422Ser is already phosphorylated (Fig. 1). Phosphorylation of SGK1 at 422Ser promotes SGK1 binding to the PDK1 interacting fragment
(PIF)-binding pocket and phosphorylation at 256Thr by
PDK1 (31). An alternate mechanism of SGK1 activation by
PDK1 involves the scaffold protein Na⫹/H⫹ exchanger
regulating factor 2 (NHERF2). NHERF2 mediates the assembly of SGK1 and PDK1 via its PDZ domains and PIF
consensus sequence (70). NHERF2 interacts with the PDZ
binding motif of SGK1 through its first PDZ domain and
with PIF-binding pocket of PDK1 through its PIF tail. The
formation of the ternary complex facilitates the phosphorylation of SGK1 on 256Thr in its T-loop by PDK1 (70).
Most recent evidence suggests that the activation of
SGK1 by PDK1 may indirectly involve the serine/threonine kinase WNK1 (with no lysine kinase 1) (370). It is
well established that insulin-like growth factor I (IGF-I)
enhances SGK1 activity in a PI 3-kinase-dependent manner via PDK1. Recent evidence suggested a role of WNK1
in the activation of SGK1 by IGF-I (371). According to this
evidence, IGF-I induces SGK1 activity by stimulating
WNK1 phosphorylation at 58Thr, a site that is phosphorylated by protein kinase B (PKB/Akt). The PI 3-kinasedependent step in the activation of SGK1 by IGF-I was
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otropins (68, 129, 263, 264, 278), 1,25-dihydroxyvitamin D3
[1,25(OH)2D3] (4), transforming growth factor-␤ (TGF-␤)
(178, 184, 352), interleukin-6 (216), fibroblast and plateletderived growth factor (222), thrombin (23), endothelin
(366), as well as other cytokines (80, 182, 330). Moreover,
activation of peroxisome proliferator-activated receptor ␥
(PPAR␥) stimulates SGK1 gene transcription (146). The
human isoform has been identified as a cell volume-regulated gene that is transcriptionally upregulated by cell
shrinkage (349). In renal epithelial (A6) cells, SGK1 expression is stimulated by cell swelling rather than cell
shrinkage (272). SGK1 transcription is further stimulated
by excessive glucose concentrations (184, 275), heat
shock, ultraviolet (UV) radiation, and oxidative stress
(198).
SGK1 transcription is inhibited by heparin (90) and
by mutations in the gene MECP2, which underlies Rett
syndrome (RTT), a disorder with severe mental retardation (237). Intestinal SGK1 transcription is further regulated by dietary iron (212).
Signaling molecules involved in the transcriptional
regulation of SGK1 include protein kinase C (184, 222),
the protein kinase Raf (222), mammalian mitogen-activated protein kinase (BMK1) (137), mitogen-activated
protein kinase (MKK1) (85, 222), stress-activated protein
kinase-2 (SAPK2, p38 kinase) (24, 64, 351), phosphatidylinositol (PI) 3-kinase (129), cAMP (129, 170), and p53
(207, 209). Moreover, SGK1 transcription is stimulated by
an increased cytosolic Ca2⫹ concentration (170) and by
nitric oxide (321).
SGK1 transcript levels are increased by ischemia of
brain (236) and kidney (108). SGK1 expression is decreased during rejection of transplanted kidneys (329).
Leukocyte SGK1 transcript levels are enhanced by treatment with dialysis (116).
A striking increase of SGK1 expression is observed
during wound healing (164) and in fibrosing tissue, such
as diabetic nephropathy (178, 184), glomerulonephritis
(118), liver cirrhosis (110), fibrosing pancreatitis (170),
Crohn’s disease (352), lung fibrosis (360), and cardiac
fibrosis (323). SGK1 gene transcription is stimulated by
DNA damage through p53 and activation of extracellular
signal-regulated kinase (ERK1/2) (222, 375), and is also
upregulated after neuronal injury (159), neuronal excitotoxicity (145), and neuronal challenge by exposure to
microgravity (84).
The promoter of the rat SGK1 gene carries several
putative and confirmed transcription factor binding sites
including those for the glucocorticoid receptor (GR), the
mineralocorticoid receptor (MR), the progesterone receptor (PR), the vitamin D receptor (VDR), the retinoid X
receptor (RXR), the farnesoid X receptor (FXR), the sterol regulatory element binding protein (SREBP), PPAR␥,
the cAMP response element binding protein (CREB), the
p53 tumor suppressor protein, the Sp1 transcription fac-
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thus suggested to be the PDK1-dependent activation of
PKB/Akt and the subsequent phosphorylation of WNK1 at
58
Thr (371). Neither the catalytic activity nor the kinase
domain but the NH2-terminal 220 residues of WNK1 are
required for activation of SGK1 (371). WNK1 binds SGK1
directly but does not phosphorylate it, suggesting that
WNK1 serves as a scaffold protein to assemble other
molecules required for maximal SGK1 activation. Its
phosphorylation at 58Thr by PKB/Akt may induce binding
of accessory proteins or a conformational change in SGK1
that stimulates the kinase. However, further experimental
evidence is needed to elucidate how WNK1 phosphorylation promotes SGK1 activation.
SGK2 and SGK3 may similarly be activated by PDK1
and PDK2/H-motif kinase. The equivalent phosphorylation
sites for SGK2 and SGK3 are predicted to be at 193Thr/356Ser
and 253Thr/419Ser, respectively, but this requires further investigation. The kinases are also regulated by WNK1, although to a lesser extent than SGK1 (371).
Replacement of the serine at position 422 by aspartate in the human SGK1 leads to the constitutively active
S422D
SGK1 (172), whereas replacement of lysine at position 127, within the ATP-binding region required for enzymatic activity, with asparagine leads to the inactive
Physiol Rev • VOL
K127N
SGK1 (172). Analogous mutations in the human
SGK2 and SGK3 lead to the constitutively active
S356D
SGK2 and S419DSGK3 and the constitutively inactive
K64N
SGK2 and K191NSGK3 (41).
In part through the PI 3-kinase pathway, SGK1 is
activated by insulin (171, 254), IGF-I (137, 171, 179), hepatic growth factor (HGF) (287), and follicle stimulating
hormone (FSH) (265).
SGK1 can be activated by bone marrow kinase/extracellular signal-regulated kinase 5 (BK/ERK5) or by p38␣.
The kinases do not phosphorylate SGK1 at 256Thr but at
78
Ser, which is outside the catalytic domain (137, 216).
How this phosphorylation activates SGK1 is not known.
SGK1 can also be activated by an increase of cytosolic
Ca2⫹ activity, an effect presumably mediated by calmodulin-dependent protein kinase kinase (CaMKK) (158).
Moreover, the small G protein Rac1 activates SGK1 via a
PI 3-kinase-independent pathway (287). Additional activators of SGK1 include neuronal depolarization (179), cAMP
(179, 254, 315), lithium (179), oxidation (171, 256), and
adhesion to fibronectin (287).
Similar to SGK1, SGK2 and SGK3 are activated by
oxidation, insulin, and IGF-I through a signaling cascade
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⫹
⫹
FIG. 1. Left: model for the Serum- and Glucocorticoid-inducible Kinase-1 (SGK1)-dependent regulation of Na reabsorption and K secretion
in the aldosterone-sensitive distal nephron. Aldosterone binds to mineralocorticoid receptors (MR) and stimulates the expression of SGK1,
␣-epithelial Na⫹ channel (␣ENaC), renal outer medullary K⫹ channel (ROMK), and the Na⫹-K⫹-ATPase. ␣ENaC associates with constitutive ␤- and
␥-subunits to form fully active ENaC. SGK1 can be phosphorylated on 422Ser by insulin or insulin-like growth factor I (IGF-I) through a signaling
cascade involving phosphatidylinositol 3-kinase (PI 3K) and an unknown kinase (PDK2?/hydrophobic motif kinase). Phosphorylated 422Ser allows
binding of PDK1 and/or NHERF2 with subsequent phosphorylation of SGK1 at 256Thr. PDK1 might activate SGK1 indirectly through phosphorylation
of WNK1 kinase. Phosphorylated 422Ser allows binding of PDK1 and/or NHERF2 with subsequent phosphorylation of SGK1 at 256Thr. PDK1 might
activate SGK1 indirectly through phosphorylation of WNK1 kinase. The mechanism of SGK1 activation by WNK1 is yet unknown but does not require
SGK1 phosphorylation. Activated SGK1 increases Na⫹ reabsorption in part by phosphorylation of the ubiquitin ligase Nedd4 –2, allowing binding of
the chaperone 14 –3-3 to phosphorylated 444Ser. This interaction prevents Nedd4 –2-mediated ubiquitination of the ENaC-PY motif and thus
internalization and degradation of ENaC. SGK1 further stimulates ENaC by upregulation of transcription, by direct phosphorylation of the channel
protein, and by inhibition of the inducible nitric oxide synthase (iNOS). In addition to its effect on ENaC, SGK1 stimulates the Na⫹-K⫹-ATPase and
K⫹ channels including ROMK. Right: arithmetic means ⫾ SE of ENaC-induced currents in Xenopus oocyte coexpression experiments showing that
coexpression of wild-type SGK1 but not of the inactive mutant K127NSGK1 leads to stimulation of an ENaC mutant lacking the SGK1 phosphorylation
consensus sequence (S622AENaC).
FUNCTIONAL SIGNIFICANCE OF SGK ISOFORMS
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mineralocorticoid excess, an assumption supported by
observations in SGK1 knockout animals.
C. Degradation of SGKs
A. Ion Channels
SGK1 is rapidly degraded, with a half-life of 30 min
(50). Ubiquitination of SGK1 labels the kinase for degradation by the proteasome (50). SGK1 degradation may be
mediated by the ubiquitin ligase Nedd4 –2 (neuronal precursor cells expressed developmentally downregulated)
(386). Nedd4 –2 contains a series of tryptophan-rich sequences (WW motifs) that interact with a proline-tyrosine
PY motif present in its target proteins. SGK1 bears such a
PY motif. Overexpression of Nedd4 –2 decreases steadystate levels of SGK1 in a dose-dependent manner by increasing SGK1 ubiquitination (presumably within the first
60 NH2-terminal amino acids) and subsequent degradation in the 26S proteasome. Conversely, silencing of
Nedd4 –2 by RNA interference, or loss of the NH2-terminal
amino acids, abrogates the ubiquitination and thus increases the half-life of SGK1. The effect of Nedd4 –2 apparently requires phosphorylation of the ubiquitin ligase
by SGK1, as SGK1 degradation is reduced by a phosphorylation site-deficient Nedd4 –2 mutant (Nedd4 –2S/T-A) or
by SGK1 inhibition (Fig. 1). Accordingly, active SGK1
favors its own degradation, thus contributing to the limitation of its action (386).
1. Epithelial Na⫹ channel ENaC
III. ROLE OF SERUM- AND GLUCOCORTICOIDINDUCIBLE PROTEIN KINASES IN THE
REGULATION OF MOLECULAR AND
CELLULAR FUNCTIONS
The SGK1 kinase consensus sequence has been defined as R-X-R-X-X-(S/T)-␾, where X stands for any amino
acid, R for arginine, and ␾ indicates a hydrophobic amino
acid (31, 75, 119, 171, 205, 224, 235, 249). It shares the
consensus sequence with PKB/Akt and with the SGK2 and
SGK3 isoforms. By direct phosphorylation of effector
molecules or by regulators thereof, SGK1 modifies a variety of cellular functions in virtually every organ.
It should be kept in mind that most experiments
demonstrating SGK1-dependent phosphorylation, or regulation of target proteins, have employed overexpression
of the kinase, and the results do not necessarily reflect the
physiological function of the kinase. As a matter of fact,
the only targets hitherto shown to be exclusively phosphorylated by SGK1 are N-myc downregulated genes
NDRG1 and NDRG2 (227, 229), proteins with ill-defined
function. Thus the regulation of most physiological functions listed below involves but is not exclusively accomplished by the SGK isoforms. SGK1-dependent regulation
may become particularly important following genomic
upregulation of the kinase, e.g., under glucocorticoid or
Physiol Rev • VOL
The potent transcriptional regulation of SGK1 by
mineralocorticoids (29, 49, 65, 95, 128, 206, 213, 226, 231,
290, 316) suggests a role of this kinase in the control of
epithelial Na⫹ transport. A key channel in the mineralocorticoid regulation of renal tubular Na⫹ reabsorption is
epithelial Na⫹ channel (ENaC) (59, 206) (Fig. 1). As described elsewhere in more detail (250, 331), SGK1 interacts with ENaC (355), and coexpression of SGK1 indeed
markedly enhances the activity of ENaC heterologously
expressed in Xenopus oocytes (10, 44, 65, 67, 184, 231,
341, 345), cortical collecting duct cells (138, 233), and A6
cells (11, 13, 105).
SGK1 has been suggested to modulate ENaC activity
directly by channel phosphorylation (91). On the other
hand, overexpression of constitutively active Xenopus
S425D
SGK1 in A6 cells did not significantly increase the
phosphorylation of any of the three subunits of ENaC
(13). Thus the effect of SGK1 on ENaC phosphorylation
requires further experimental support. In any case, SGK1
may regulate ENaC indirectly by phosphorylating the
ubiquitin ligase Nedd4 –2 (17, 86, 113, 243, 298, 299, 341,
386), which otherwise ubiquitinates ENaC thus preparing
the channel protein for clearance from the cell membrane
and subsequent degradation (302) (Fig. 1). The phosphorylation of Nedd4 –2 decreases the ability of Nedd4 –2 to
ubiquitinate ENaC, and SGK1 thus increases the abundance of ENaC channel protein within the cell membrane
(10, 165, 184, 345). Mutations of Nedd4 –2 affecting the PY
motif of ENaC may disrupt Nedd4 –2 dependent degradation of the channel and thus lead to excessive renal salt
reabsorption and arterial hypertension (3, 94, 131, 166,
281, 303). The naturally occurring human P355LNedd4 –2
variant, found in patients with end-stage renal disease
(ESRD) that suffered from arterial hypertension, was
shown to be more sensitive to phosphorylation by SGK1
and, accordingly, to exert a weaker negative effect on
ENaC (114).
SGK1-mediated phosphorylation of Nedd4 –2 induces
its interaction with members of the 14 –3-3 family of regulatory proteins. Interaction of Nedd4 –2 with 14 –3-3 inhibits Nedd4 –2-dependent ubiquitination of its targets
(28, 156) (Fig. 1). Overexpression of the chaperone 14 –3-3
decreases, whereas expression of a transdominant inhibitory mutant of 14 –3-3 increases the Nedd4 –2-dependent
ubiquitination of ENaC (28, 156). The prominent expression of 14 –3-3 proteins in collecting duct principal cells
suggests a physiological role for these proteins in the
regulation of distal nephron Na⫹ transport (28). It should
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involving PI 3-kinase as well as PDK1 and PDK2/H-motif
kinase (171, 335).
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2. Renal outer medullary K⫹ channel ROMK1
Aldosterone stimulates not only the renal reabsorption of Na⫹, but also the renal excretion of K⫹ (347).
Renal tubular K⫹ secretion has been thought to be accomplished by ROMK1 (6, 126, 347, 357), which is, similar to
ENaC and SGK1, expressed in the principal cells of the
aldosterone-sensitive distal nephron (342) (Fig. 1). Thus
ROMK1 appeared to be an obvious target for regulation by
SGK1. Indeed, ROMK1 is upregulated by coexpression of
SGK1 in Xenopus oocytes, an effect in part due to enhanced channel protein abundance at the plasma membrane (245, 374, 380). However, full effect of SGK1 on
ROMK1 requires the NHERF2 (245, 380), a protein that
allows trafficking of carriers and channels to the cell
membrane (288, 378) and that is similarly expressed in
principal cells of the aldosterone-sensitive distal nephron
(288). Coexpression of ROMK1 together with NHERF2,
but neither SGK1 nor NHERF2 alone, leads to profound
upregulation of ROMK1 channel activity (380). PresumPhysiol Rev • VOL
ably, the binding of ROMK1 to NHERF2 involves a
postsynaptic density 95, disk large, zona occludens-1
(PDZ)-binding motif at the COOH terminus of ROMK1
(245). The ENaC sequence does not include a PDZ-binding motif, suggesting that NHERF2 cannot directly interact with ENaC. On the other hand, the sequence of
ROMK1 does not include a PY motif that is thought to be
required for binding of Nedd4 –2 to its targets (86). Besides its effect on ROMK1 surface abundance, SGK1 directly phosphorylates ROMK1 (244, 374, 380). Phosphorylation introduces a negative charge and leads to a
marked shift of ROMK1’s pH sensitivity, resulting in enhanced activity of the channel at the usual cytosolic pH
(244).
3. Renal epithelial Ca2⫹ channel TRPV5
As shown in Xenopus oocytes, SGK1 and SGK3 activate the renal epithelial Ca2⫹ channel TRPV5 by enhancing channel abundance in the plasma membrane, an effect
again requiring cooperation with NHERF2 (101, 246). The
TRPV5 C-tail interacts in a Ca2⫹-independent manner
with NHERF2. Deletion of the second, but not the first,
PDZ domain in NHERF2 abrogates the stimulating effect
of SGK1 on TRPV5 protein abundance (246).
4. Renal and inner ear Cl⫺ channel ClC-Ka
In Xenopus oocytes SGK1, SGK2, and SGK3 upregulate the Cl⫺ channel complex ClC-Ka/barttin (99). Similar
to the mechanism involved in SGK1-dependent regulation
of ENaC, SGK1 enhances ClC-Ka/barttin protein abundance and activity in part by phosphorylation of Nedd4 –2.
The ubiquitin ligase downregulates ClC-Ka/barttin, an effect abrogated by a mutation of barttin (Y98Abarttin) that
eliminates the PY motif. However, the Y98Abarttin mutation blunts, but does not abrogate, the regulation of
ClC-Ka by SGK1, pointing to Nedd4 –2-independent mechanisms of ClC-Ka/barttin regulation by SGK1.
5. Ubiquitous Cl⫺ channel ClC2
In Xenopus oocytes SGK1, SGK2, and SGK3 enhance
the activity and surface abundance of the cell volumeregulated Cl⫺ channel ClC2 (242). The kinases do not
modulate the activity of the channel directly, as the deletion of the SGK1 phosphorylation site in the ClC2 protein
does not abrogate SGK1-dependent stimulation of the
channel. Instead, SGKs stimulate ClC2 by inhibiting
Nedd4 –2, leading to reduced clearance of ClC2 protein
from the cell membrane.
6. Cystic fibrosis transmembrane conductance
regulator Cl⫺ channel CFTR
In Xenopus oocytes, SGK1 activates the Cl⫺ currents
induced by the cystic fibrosis transmembrane conduc-
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be pointed out that phosphorylation of Nedd4 –2 is not an
exclusive function of SGK1, as it is observed even in the
absence of the kinase (113) and upon coexpression of
SGK3 in Xenopus oocytes (243). Although SGK1 shares
the consensus sequence with its isoforms SGK2, SGK3,
and the related kinase PKB/Akt, the phosphorylation efficiency differs between the kinases. This was shown in
expression studies in Xenopus oocytes, which revealed
that SGK1 and SGK3 phosphorylate Nedd4 –2 more efficiently than SGK2 (243). Nedd4 –2 is likewise phosphorylated and thereby inhibited by cAMP-dependent protein
kinase (PKA) (298). The SGK1 consensus sequence overlaps with a PKA consensus sequence (R-X-X-S/T) and, in
fact, the Nedd4 –2 residues found to be phosphorylated by
PKA (221Ser, 246Thr, and 327Ser) are also phosphorylated
by SGK1. Nedd4 –2 contains additional PKA motifs that
might be phosphorylated but are not responsible for the
inhibition of Nedd4 –2 by PKA (298). The relative functional contribution of the three phosphorylation sites to
PKA- and SGK1-dependent regulation of Nedd4 –2 activity
is not identical (298). Similar to SGK1, PKA altered ENaC
surface expression by modulating the function of
Nedd4 –2 (298). Thus PKA and SGK1 might regulate ENaC
in part through convergent phosphorylation of Nedd4 –2
(298).
Beyond its effect on ENaC activity and Nedd4 –2
phosphorylation, SGK1 stimulates ENaC transcription
(47) (Fig. 1). Moreover, SGK1 may inhibit inducible nitric
oxide synthase, and the decreased formation of nitric
oxide may then disinhibit ENaC (139).
In the Xenopus oocyte system, the effect of SGK1
expression on ENaC is shared by SGK2 and SGK3 (117),
which may, however, not be relevant for regulation of
renal salt excretion (see below).
FUNCTIONAL SIGNIFICANCE OF SGK ISOFORMS
tance regulator (CFTR) (345). Given the marked upregulation of SGK1 in inflammatory lung disease (360), this
effect could participate in the stimulation of bronchial
Cl⫺ secretion and/or reabsorption during lung infection.
7. Cardiac voltage-gated Na⫹ channel SCN5A
8. Cardiac and epithelial K⫹ channels KCNE1/KCNQ1
The K⫹ channel complex KCNE1/KCNQ1 is expressed in several tissues including heart and kidney
(311). It activates slowly upon depolarization (311). As
has become apparent from heterologous expression studies in Xenopus oocytes, the current is markedly upregulated by coexpression with SGK1, SGK2, and/or SGK3
(100). Again, part of the effect is due to phosphorylation
of Nedd4 –2 (100). The effects of SGK1 on KCNE1/KCNQ1
are expected to shorten the cardiac action potential and
may influence transport in KCNE1-/KCNQ1-expressing
epithelia (see below).
⫹
9. Inner ear K channels KCNQ4
KCNQ4 is expressed in inner and outer hair cells of
the inner ear where it determines electrical excitability.
The critical role of KCNQ4 in hearing function is underlined by the fact that loss-of-function mutations of the
KCNQ4 gene cause hearing loss (148, 176, 211). SGK1
significantly increases peak KCNQ4 activity and also modulates the influence of previous channel activation (284).
These effects were sensitive to mutations in the SGK1
consensus sequence of the channel. In theory, through its
effect on KCNQ4, SGK1 could contribute to the known
beneficial effect of glucocorticoids in hearing loss or vertigo (15, 144, 292).
10. Voltage-gated K⫹ channels Kv1.3, Kv1.5,
and Kv4.3
As is apparent from Xenopus oocyte expression system studies, SGK1, SGK2, and SGK3 enhance the K⫹
current induced by the voltage-gated K⫹ channels Kv1.3
(124, 140, 359), Kv1.5 (322), and Kv4.3 (21). Similarly,
Physiol Rev • VOL
overexpression of PDK1, SGK1, SGK2, or SGK3 in human
embryonic kidney (HEK) cells leads to marked upregulation of K⫹ channels with gating properties identical to
Kv1.3 (123, 124, 359). The same channels are activated by
treatment of the HEK cells with IGF-I, an effect reversed
by inhibition of PI 3-kinase (124). Kv channel activity is
seemingly normal in fibroblasts from gene-targeted mice
lacking functional SGK1 (sgk1⫺/⫺), but cannot be regulated by serum or glucocorticoids (293). Accordingly, in
contrast to fibroblasts from wild-type animals, fibroblasts
from sgk1⫺/⫺ mice do not significantly decrease Kv channel activity after serum depletion and do not significantly
increase Kv channel activity after treatment with dexamethasone, IGF-I, or both (293).
11. Cation channels created by 4F2/LAT
The expression of the heterodimeric amino acid
transporter 4F2/LAT in Xenopus oocytes not only induces
amino acid transport, but also a cation conductance (344).
This cation conductance, but not the amino acid transport, is upregulated by coexpression with SGK1 (344).
12. Glutamate receptors
SGK1 increases the insertion of the kainate receptor
GluR6 into the cell membrane (308), whereas SGK3 stimulates the ␣-amino-3-hydroxy-5-methyl-4-isoxazolic acid
(AMPA) receptor GluR1 (307). Thus both kinases could
participate in the regulation of neuroexcitability.
B. Carriers and Pumps
1. Na⫹/H⫹ exchanger NHE3
SGK1 increases NHE3 activity, an effect requiring the
scaffold protein NHERF2 (379). The kinase is effective
through phosphorylation of the carrier protein at Ser-663
(353). The increased NHE3 activity is associated with an
increased amount of carrier proteins in the surface membrane (353). NHE3 participates in Na⫹ reabsorption and
H⫹ secretion in a variety of epithelia and contributes to
the regulation of cytosolic pH in a number of epithelial
and nonepithelial cells (346).
2. Glucose transporters
SGK1 has been shown to stimulate the activity of the
Na⫹-glucose cotransporter SGLT1 (93) and the facilitative
glucose transporter GLUT1 (241). On the other hand,
overexpression of SGK1 failed to enhance glucose uptake
into 3T3-L1 cells (276). Regulation of SGLT1 (93), but not
GLUT1 (241), by SGK1 is at least partially mediated by
phosphorylation of Nedd4 –2. The mechanisms underlying
the SGK1-dependent regulation of GLUT1 remain ill-defined (241).
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In Xenopus oocytes, both SGK1 and SGK3 stimulate
the cardiac voltage-gated Na⫹ channel SCN5A (42).
SCN5A has previously been shown to be downregulated
by Nedd4 (2). Accordingly, inhibition of Nedd4 most
likely participates in the regulation of the channel by
SGKs. However, the kinases modify the gating kinetics of
SCN5A channels, an effect which cannot be explained by
delayed retrieval from the cell membrane (42). At this
stage it is not clear whether SGK1 phosphorylates SCN5A.
Interestingly, replacement by site-directed mutagenesis of
the serine at the putative SGK consensus sequence by
alanine leads to an opposite shift of the gating properties
of the channel (42).
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LANG ET AL.
3. Amino acid transporters
SGK1 has been shown to upregulate a variety of
amino acid transporters including ASCT2 (SLC1A5) (247),
the glutamine transporter SN1 (40), as well as the glutamate transporters EAAT1 (39), EAAT2 (37), EAAT3 (283),
EAAT4 (43), and EAAT5 (41). Upregulation of amino acid
transporters has also been shown by SGK2 and SGK3 (37,
39 – 41, 246, 283).
4. Na⫹-dicarboxylate cotransporter NaDC-1
5. Creatine transporter CreaT
D. Transcription Factors
Both SGK1 and SGK3 stimulate the activity of CreaT
(SLC6A8), and this effect is partially mediated by interference with Nedd4 –2 activity (291).
6. Phosphate carrier
Coexpression of SGK1 enhances the activity of the
intestinal Na⫹-phosphate cotransporter NaPiIIb, an effect
at least partially accounted for by phosphorylation of
Nedd4 –2 (243). The proximal renal tubular phosphate
transporter NaPiIIa was, however, shown to be insensitive to SGK1 coexpression (381).
7. Na⫹-K⫹-ATPase
In the kidney, SGK1 colocalizes with the Na⫹-K⫹ATPase (12). In Xenopus oocytes, expression of SGK1
increases the activity of both endogenous (285) and exogenous (332, 381) Na⫹-K⫹-ATPase. The effect is at least
partially due to enhanced Na⫹-K⫹-ATPase abundance in
the cell membrane (381). The ability to modulate Na⫹-K⫹ATPase activity is shared by the SGK2 and SGK3 isoforms
(141).
C. Enzyme Activities
As discussed above, SGK1 phosphorylates Nedd4 –2,
thus interfering with the binding of the ubiquitin ligase to
its targets (17, 86, 298, 299, 386).
SGK1 further phosphorylates, and thus inhibits, glycogen synthase kinase 3 (GSK3) (276). Accordingly, SGK1
may abrogate the effect of this kinase on glycogen synthase. Moreover, it may modify the many cellular functions under control of this important signaling molecule
(74), including inhibition of matrix protein formation (see
below). However, studies with a PDK1 mutant mouse
with a disrupted PIF-binding docking site, which activates
PKB/Akt but not SGK (75), suggest that GSK3 is usually
regulated by PKB/Akt rather than SGK.
Physiol Rev • VOL
SGK1 associates with and phosphorylates the cAMP
responsive element binding protein (CREB) and thus interferes with CREB-dependent gene transcription (83).
Moreover, SGK1 enhances the activity of NF␬B (384) by
association with and activation of I␬B kinase beta (IKK␤)
(384). SGK1 enhances the ability of IKK␤ to phosphorylate I␬B␣, leading to degradation of I␬B and thus NF␬B
activation (384) (Fig. 2).
SGK1 phosphorylates the forkhead transcription factor FKHR-L1 (FOXO3a) leading to disruption of FKHR-L1dependent transcription, cell cycle arrest, and apoptosis
(375). However, similar to what has been discussed above
for GSK3, studies with a PKB/Akt, but not SGK1, activating PDK1 mutant mouse (75) suggest that FKHR-L1 is
usually regulated by PKB/Akt rather than by SGK1.
At least in keratinocytes, SGK3 interferes with the
Lef-1/␤-catenin transcription pathway, as nuclear accumulation of ␤-catenin is deranged in keratinocytes from
gene-targeted mice lacking functional SGK3 (214).
E. Release of Hormones
Pancreatic ␤-cells express negligible amounts of
SGK1 under normal conditions (170, 322). However, treatment with glucocorticoids markedly upregulates SGK1
expression (322). SGK1 in turn upregulates the voltagesensitive Kv1.5 channels. These channels lead to more
rapid repolarization of depolarized ␤-cells, and thus blunt
the Ca2⫹ increase during stimulation (322). As a result,
SGK1 contributes to, or even accounts for, the acute
inhibitory effect of glucocorticoids on insulin release.
Plasma aldosterone concentration is enhanced in
SGK1 knockout mice (368). The hyperaldosteronism is
presumably the adequate response to extracellular volume depletion (see below) rather than due to a more
direct role of SGK1 in the regulation of aldosterone release.
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As shown in Xenopus oocytes, NaDC-1 is stimulated
by SGK1 and SGK3, an effect requiring the participation of
NHERF2 (38).
SGK1 phosphorylates and thus inhibits mitogen-activated protein kinase/ERK kinase kinase 3 (MEKK3),
which is activated following exposure to growth factors,
oxidative stress, and hyperosmotic stress (69). Thus SGK1
may interfere with MEKK3-dependent cellular functions,
which signal to the transcription factors NFAT and NF␬B
(1, 36, 62).
SGK1 phosphorylates and inactivates the B-Raf kinase (382) and may thus interfere with B-Raf kinasedependent cellular functions, which are critical for stimulation of cell proliferation by growth factors (19, 301).
SGK1 phosphorylates and thereby inhibits the phosphomannose mutase 2 (218). SGK1 may thus interact with
the glycosylation of glycoproteins (218).
FUNCTIONAL SIGNIFICANCE OF SGK ISOFORMS
1159
G. Cell Proliferation and Apoptosis
2. Role of SGK1 in the control of the nuclear factor NF␬Bdependent gene regulation and fibrosis. SGK1 phosphorylates and thus
activates the kinase I␬B kinase beta (IKK␤), which subsequently phosphorylates (P) the inhibitor I␬B of NF␬B. The phosphorylation of I␬B
leads to dissociation of the I␬B-NF␬B complex. I␬B is subsequently
ubiquitinated (Ub) and degraded, whereas NF␬B travels into the nucleus
to turn on gene transcription. NF␬B-dependent genes include connective tissue growth factor (CTGF), an important stimulator of matrix
protein synthesis and fibrosis.
FIG.
The plasma concentrations of parathyroid hormone
and of 1,25(OH)2D3 have been shown to be similar in
SGK1 knockout mice and their wild-type littermates
(280).
F. Regulation of Cell Volume
SGK1 is strongly upregulated by osmotic and isotonic
cell shrinkage (349). In contrast, SGK1 expression is stimulated by swelling of A6 cells (272). It is tempting to
speculate that SGK1-dependent regulation of cation channels contributes to the regulation of cell volume, which
involves cation channels in a variety of cells (61, 97, 125,
153, 173, 187, 188, 337, 363). The entry of Na⫹ through
nonselective cation channels depolarizes the cells, thus
favoring parallel entry of Cl⫺. The entry of NaCl and the
osmotically obliged water then allows regulatory cell volume increase (181). Interestingly, dexamethasone, which
Physiol Rev • VOL
Both SGK1 (53, 287, 384) and SGK3 (203, 372) have
been shown to confer cell survival. The antiapoptotic
effect of SGK1 and SGK3 has been attributed in part to
phosphorylation of forkhead transcription factors (53,
203, 372), such as FKRHL1 (287). Moreover, SGK3 has
been shown to phosphorylate and thus inactivate Bad
(203, 372). Phosphorylated Bad binds to the chaperone
14 –3-3 and is thus prevented from traveling to the mitochondria, where it triggers apoptosis (204).
Activation of SGK1 in Madin-Darby canine kidney
(MDCK) cells by adhesion to fibronectin provided an
antiapoptotic signal (287). Following detachment, the survival of MDCK cells was compromised but could be maintained by activation of SGK1 with HGF (287).
SGK1 has further been shown to inhibit apoptosis of
breast cancer cells (384). In those cells SGK1 exerted its
effects by modulating NF␬B (384). Accordingly, SGK1dependent cell survival was abolished by a dominant
negative form of IKK␤ or knockout of IKK␤ (384). On the
other hand, SGK1 apparently does not share the capability
of PKB/Akt to phosphorylate Bax, and thus to prevent the
targeting of this important proapoptotic factor to the
mitochondria (320).
Proliferative signals appear to shuttle SGK1 into the
nucleus (55, 112). The effect of SGK1 and SGK3 on cell
proliferation may further involve their ability to regulate
Kv1.3 (Fig. 3). The upregulation of Kv1.3 channel activity
may be important for the proliferative effect of growth
factors, as IGF-I-induced cell proliferation is disrupted by
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stimulates the transcription of SGK1 (361, 362), enhances
the stimulating effect of osmotic cell shrinkage on cation
channels in macrophages (125). However, the molecular
identity of these channels and the mechanisms of their
regulation by glucocorticoids and osmotic cell shrinkage
have remained elusive. Thus the functional significance of
SGK1 in the stimulation of cation channels and in cell
volume regulation remains to be established.
SGK1 has been shown to activate the volume-sensitive osmolyte and anion channel (VSOAC) (354). In Xenopus oocytes, SGK1 enhances the activity of the cell volume-regulated Cl⫺ channel ClC2 (242). Activation of
those channels leads to the exit of Cl⫺ and cell membrane
depolarization, which in turn favors exit of K⫹. The cellular loss of KCl leads to regulatory cell volume decrease.
Those observations are in seeming contrast to the strong
genomic upregulation of SGK1 by cell shrinkage (349) and
would suggest a role of SGK1 in regulatory cell volume
decrease rather than in regulatory cell volume increase.
Possibly, the genomic upregulation of SGK1 during cell
shrinkage serves to increase the ability of the cell to cope
with alterations of cell volume in either direction.
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LANG ET AL.
several blockers of Kv channels (124). Stimulation of K⫹
channels by mitogenic factors and correlation of K⫹ channel activity with proliferation has been demonstrated in a
variety of cells (201, 239, 266, 300). K⫹ channels are
thought to be important for the maintenance of the cell
membrane potential (Fig. 3), which is in turn required for
proper function of the Ca2⫹ release-activated Ca2⫹ channel (ICRAC) (248). The latter channel mediates Ca2⫹ entry
upon stimulation of cells with a wide variety of mitogenic
factors, a prerequisite for triggering cell proliferation (27).
Both Kv1.3 channels (134, 310) and ICRAC (200) are inhibited by stimulation of CD95, a receptor, which among
other functions, disrupts activation and triggers apoptosis
of lymphocytes (181, 185).
The SGK1 knockout mice show seemingly normal
development (368). Thus SGK1 is either not a crucial
element in the regulation of cell proliferation or apoptosis, or related kinase(s) can effectively replace SGK1
function in the SGK1 knockout mice.
Impaired proliferation and enhanced apoptosis of
keratinocytes were observed in gene-targeted mice lacking functional SGK3, leading to delayed hair growth (9,
214).
H. Other Functions
SGK1 has been shown to participate in the osmotic
regulation of the type A natriuretic peptide receptor
(NPR-A). The receptor is upregulated by osmotic shrinkage through a signaling pathway involving p38 kinase and
SGK1 (64). SGK1 has further been shown to phosphorylate the Ca2⫹-regulated heat-stable protein of apparent
molecular mass 24 kDa (CRHSP24) (18).
Physiol Rev • VOL
As mentioned before, target proteins specifically
phosphorylated by SGK1 (and not by PKB/Akt) are
NDRG1 and NDRG2 (227, 229). The phosphorylation by
SGK1 primes the protein for phosphorylation by GSK3
(227). The functional impact of SGK1-dependent phosphorylation of NDRG1 and NDRG2, however, remains
elusive. NDRG2 is a transcriptional target of mineralocorticoids, pointing to some role in the regulation of salt
balance (46).
SGK1 has further been shown to phosphorylate filamin C (228) and the microtubule-associated protein tau
(71). SGK1 forms together with tau and the protein 14 –3-3
a ternary protein complex leading to phosphorylation of
tau (71). As described below, hyperphosphorylation of
tau is a typical feature of Alzheimer’s disease.
IV. ROLE OF SERUM- AND GLUCOCORTICOIDINDUCIBLE PROTEIN KINASES IN THE
REGULATION OF INTEGRATED FUNCTIONS
A. Metabolism
When expressed in Xenopus oocytes, SGK1 and
SGK3 have been shown to stimulate the activity of the
Na⫹-glucose cotransporter SGLT1 (93), which serves to
absorb intestinal glucose. Notably, sgk1⫺/⫺ mice show
reduced glucocorticoid-induced intestinal glucose uptake
(132), whereas sgk3⫺/⫺ mice actually exhibit decreased
basal intestinal glucose transport (279). At least partially
due to its stimulating effect on glucose transporter GLUT1
(241), SGK1 also favors cellular glucose uptake from the
circulation into several tissues including brain, fat, and
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⫹
2⫹
FIG. 3. Middle: putative role of SGK1 in the regulation of K and Ca
channels required for stimulation of cell proliferation. Mitogenic factors
stimulate the Ca2⫹ release-activated Ca2⫹ channel ICRAC. Ca2⫹ entry through this channel is highly sensitive to cell membrane potential, which is
⫹
⫹
maintained by K channels. The stimulation of the voltage-sensitive K channel Kv1.3 by SGK1 may serve to maintain the cell membrane
polarization and thus sustain oscillating Ca2⫹ entry through ICRAC. Left: current generated by depolarization of HEK cells overexpressing
constitutively active S422DSGK1 (sgk-SD) or the inactive K127NSGK1 mutant (sgk-KN). Right: peak Ca2⫹ concentration after Ca2⫹ entry in
Ca2⫹-depleted fibroblasts from wild-type mice (sgk1⫹/⫹, open bars) or SGK1 knockout mice (sgk1⫺/⫺, solid bars) fibroblasts. Ca2⫹ entry in sgk1⫺/⫺
fibroblasts is not sensitive to serum deprivation or to dexamethasone ⫹ IGF-I. [Data modified from Shumilina et al. (293).]
FUNCTIONAL SIGNIFICANCE OF SGK ISOFORMS
B. Kidney Function and Salt Appetite
The ability of SGK1 to stimulate ENaC, ROMK1, ClCKa, TRPV5, and presumably further renal epithelial ion
channels is expected to affect renal electrolyte excretion
(for reviews, see Refs. 306, 327, 328).
The regulation of ENaC by SGK1 (Fig. 1) is considered to participate in the regulation of renal Na⫹ excretion by aldosterone, insulin, and IGF-I (33, 34, 355). While
the effect of aldosterone is only partially dependent on
the presence of SGK1, and effects of aldosterone and
SGK1 are additive, antidiuretic hormone (ADH) or insulin
does not further stimulate ENaC in cells expressing active
SGK1 (16). The latter findings indicate that activation of
ENaC by ADH or insulin depends on SGK1 and/or reflects
Physiol Rev • VOL
independent pathways induced by ADH/insulin and SGK1
that converge on the same target structures, e.g., ENaC or
Nedd4 –2 phosphorylation (298).
Experiments in SGK1 knockout (sgk1⫺/⫺) mice indeed revealed subtle but relevant impairment of renal salt
retention (368). Under normal salt supply arterial blood
pressure as well as salt intake and excretion are virtually
identical in the sgk1⫺/⫺ mice and their wild-type littermates (sgk1⫹/⫹). However, the plasma aldosterone concentration is significantly higher in sgk1⫺/⫺ mice fed a
normal Na⫹ and K⫹ diet. This may point to impaired
regulation of renal Na⫹ reabsorption (368) or reflect an
impairment of renal K⫹ secretion, which also depends on
ENaC-mediated Na⫹ reabsorption (see below). Moreover,
a NaCl-deficient diet discloses the impaired ability of the
sgk1⫺/⫺ mice to adequately lower renal Na⫹ output. Even
though NaCl excretion decreases substantially under
NaCl depletion in both sgk1⫺/⫺ and sgk1⫹/⫹ mice, the
renal NaCl loss remains significantly larger in sgk1⫺/⫺
mice than in sgk1⫹/⫹ mice, despite an increase of plasma
aldosterone concentration, decrease of arterial blood
pressure, decrease of glomerular filtration rate (GFR),
and enhanced proximal tubular Na⫹ reabsorption in the
sgk1⫺/⫺ mice (368). The phenotype of the sgk1⫺/⫺ mice is
less severe than the phenotype of ENaC knockout mice
(155) and mineralocorticoid receptor knockout mice (25).
Thus renal ENaC function and renal mineralocorticoid
action are partially but not completely dependent on the
presence of SGK1 (Fig. 1).
Acute intravenous application of insulin at a superphysiological dose (under euglycemic conditions) significantly reduced fractional urinary Na⫹ excretion without
affecting blood pressure and GFR in sgk1⫹/⫹ mice, an
effect significantly blunted in sgk1⫺/⫺ mice (149). Those
experiments demonstrate a critical role for SGK1 in insulin-induced renal Na⫹ retention.
SGK2 and SGK3 are similarly able to stimulate Na⫹
channel activity in the Xenopus oocyte expression system
(117). Renal Na⫹ retention is, however, not impaired in
the SGK3 knockout mouse (214). Moreover, renal salt loss
does not appear to be more pronounced in mice lacking
both SGK1 and SGK3 (133). Thus the in vitro observations
may not necessarily reflect the in vivo function of SGK2
and SGK3.
Lack of SGK1 further affects the ability to excrete a
K⫹ load. Despite increased basal plasma aldosterone levels, the ability of sgk1⫺/⫺ mice to excrete an acute K⫹
load is reduced. Moreover, sgk1⫺/⫺ mice excrete a
chronic K⫹ load only after marked increases of plasma K⫹
and aldosterone concentrations (151), which are two major determinants of renal K⫹ excretion. The impaired
ability of sgk1⫺/⫺ mice to excrete a chronic K⫹ load is not
due to decreased ROMK1 abundance in the luminal membrane of the distal nephron (151), but appears to be due to
a decreased electrical driving force secondary to de-
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skeletal muscle (45). Accordingly, after an intraperitoneal
glucose load, the plasma glucose concentration increases
to higher peak values and declines slower in SGK1 knockout mice (45). Likewise, the plasma glucose-lowering effect of an intraperitoneal insulin application is attenuated
in SGK1 knockout mice (45).
Salt excess, which suppresses the release of the mineralocorticoid aldosterone, impairs the peripheral glucose
uptake and thus leads to delayed decrease of plasma
glucose concentrations following a glucose load (66, 121,
333). The mechanism linking salt excess to peripheral
glucose uptake remained elusive until recently. Experiments in mice revealed that the mineralocorticoid deoxycorticosterone acetate (DOCA) restores glucose tolerance and insulin sensitivity in wild-type mice on a diet
with excess salt (45). In contrast to the observations in
wild-type animals, the glucose tolerance was not significantly modified by salt excess in SGK1 knockout mice
(45). Moreover, salt excess dissipated the differences in
glucose uptake between wild-type and SGK1 knockout
mice (45). Thus the decreased activity of SGK1 contributes to, or even accounts for, the decreased glucose tolerance during salt excess. These observations uncover a
critical role of SGK1 in the stimulation of cellular glucose
uptake by insulin. Accordingly, SGK1 does not only integrate the effects of mineralocorticoids and insulin on
renal tubular Na⫹ transport (see below) but similarly
affects glucose transport.
SGK1 further modifies carbohydrate metabolism by
phosphorylation of GSK3 and enhancement of glycogen
synthase activity in hepatocytes (276). Thus SGK1 and
SGK3 enhance intestinal glucose uptake and SGK1 helps
to transport glucose into target organs like brain, fat,
skeletal muscle, and liver. The effect of SGK1 on glucose
transport is additive to the well-known function of PKB/
Akt, which shares, along with the SGK isoforms, the
consensus sequence, the ability to stimulate glucose
transporters, and the role in the regulation of GSK3 (74).
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SGK1 mRNA is abundant in kidney medulla, and
SGK1 was shown to mediate osmotic induction of type A
natriuretic peptide receptor (NPR-A) gene promoter in
cultured cells from rat inner medullary collecting duct
(64). Thus SGK1 may contribute to cell volume regulation
in the inner medulla during osmotic challenges. Basal or
maximal urinary concentrating ability, however, is not
affected in sgk1⫺/⫺ mice (368), and thus the role of SGK1
in the inner medulla remains to be determined.
SGK1 not only participates in electrolyte balance by
its influence on renal elimination, but mediates the effect
of mineralocorticoids on salt appetite (326) . As illustrated in Figure 4, treatment of animals with the mineralocorticoid DOCA leads to excessive salt intake in wildtype mice but not in SGK1-deficient mice. Thus SGK1
plays at least a dual role in mineralocorticoid-regulated
NaCl homeostasis (Fig. 5). SGK1 dependence of both
NaCl intake and renal NaCl reabsorption suggests that
excessive SGK1 activity leads to arterial hypertension by
simultaneous stimulation of oral NaCl intake and renal
NaCl retention (see below).
C. Gastrointestinal Function
SGK1 is heavily expressed in the entire gastrointestinal tract (79) with particularly high expression in enterocytes (352). SGK1 colocalizes with Nedd4 –2 in villus enterocytes (243). The localization suggests the involvement
of SGK1 and Nedd4 –2 in the regulation of intestinal transport systems. Intestinal SGK1 transcript levels are decreased by adrenalectomy, but not increased by a single
dose of aldosterone (79). Instead, intestinal SGK1 expression may be primarily stimulated by glucocorticoids.
Intestinal function is seemingly normal in mice lacking functional SGK1 (133). However, in those mice the
stimulating effect of dexamethasone on electrogenic glucose transport and the Na⫹/H⫹ exchanger NHE3 are
blunted or even abolished (133). Those in vivo observations parallel the in vitro stimulating effect of SGK1 on the
electrogenic Na⫹-glucose cotransporter SGLT1 (93) and
on NHE3 (353, 379).
The regulation of ENaC by SGK1 in the colon is less
clear. The abundance of SGK1 in the distal colon did not
FIG. 4. Role of SGK1 in salt appetite. Daily
volume drunk from bottle 1 (tap water, left) or
from bottle 2 (tap water or 1% NaCl, right) by
SGK1 knockout mice (sgk1⫺/⫺, closed symbols)
or their wild-type littermates (sgk1⫹/⫹, open
symbols) before and during treatment with the
mineralocorticoid deoxycorticosterone acetate
(DOCA). It is demonstrated that DOCA-induced
salt appetite is significantly blunted in sgk1⫺/⫺
mice (n ⫽ 6 each group; *P ⬍ 0.05 vs. sgk1⫹/⫹).
[Modified from Vallon et al. (326).]
Physiol Rev • VOL
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creased ENaC and/or Na⫹-K⫹-ATPase activity. It may also
be the result of impaired ROMK1 channel activity or due
to decreased expression, trafficking, or activity of another
K⫹ channel.
The SGK1-sensitive voltage-gated K⫹ channel Kv1.3
(see above) is expressed in the basolateral membrane of
the inner medulla (102, 373) and presumably contributes
to K⫹ reabsorption under low K⫹ intake (373). The ability
of SGK1-deficient mice to lower urinary K⫹ excretion in
response to a low K⫹ intake appeared normal and does
not apparently require SGK1-dependent regulation of
Kv1.3 (151).
The expression of SGK1 mRNA in the kidney is not
restricted to the distal nephron but includes glomeruli,
the thick ascending limb, and possibly the early distal
convoluted and proximal tubules (for review, see Ref.
328). Recent coexpression experiments in Xenopus oocytes showed that SGK1 can activate a K⫹ channel that is
formed by KCNQ1/KCNE1 (100). In the S2 and S3 segments of the proximal tubule, this K⫹ channel mediates
K⫹ fluxes into the lumen to prevent membrane depolarization during electrogenic reabsorption of Na⫹, e.g., Na⫹glucose cotransport (324, 325). In the S2 and S3 segments
of the proximal tubule, glucose reabsorption is accomplished by the high-affinity Na⫹-glucose cotransporter
SGLT1, which is activated by SGK1 (93). Whether insulinactivated SGK1 regulates and coordinates KCNQ1/KCNE1
and SGLT1 in vivo, e.g., in response to postprandial hyperglycemia to prevent renal glucose loss, remains to be
determined.
TRPV5 Ca2⫹ channel expression is markedly decreased in mice lacking functional SGK1 (280), a finding
consistent with a stimulating effect of SGK1 on TRPV5
(101, 246). Renal Ca2⫹ excretion is, however, decreased in
sgk1⫺/⫺ mice (280), the opposite of what was expected.
Presumably, Ca2⫹ reabsorption in the proximal tubule
and in the thick ascending limb of the loop of Henle is
enhanced due to stimulation of renal tubular Na⫹ reabsorption in these nephron segments. In SGK1 knockout
animals, the stimulation of proximal tubular and loop of
Henle Na⫹ reabsorption may serve to compensate for the
defective Na⫹ reabsorption in the further distal nephron
(368).
FUNCTIONAL SIGNIFICANCE OF SGK ISOFORMS
1163
dent K⫹ channels (100), which are required for normal
intestinal glucose absorption (325). The impaired intestinal nutrient uptake may contribute to the delayed growth
of both SGK3 knockout mice (214) and SGK1/SGK3 double knockout mice (132).
D. Other Epithelia-Containing Tissues
FIG. 5. Dual role of SGK1 in the maintenance of salt homeostasis
and blood pressure. SGK1 plays a dual role in the regulation of salt
balance, i.e., in the stimulation of both renal Na⫹ reabsorption and salt
appetite. SGK1 contributes to aldosterone- and insulin-induced stimulation of renal Na⫹ reabsorption. The increased extracellular fluid volume
(ECV) enhances the cardiac output (C.O.), thus increasing mean arterial
blood pressure (MAP). The enhanced blood pressure leads to pressure
natriuresis and thus secondarily increases renal salt excretion, eventually counteracting renal salt retention. A II, angiotensin II; R, total
peripheral vascular resistance.
change significantly after Na⫹ depletion or after a single
dose of aldosterone (79). Other studies, however, reported that SGK1 mRNA levels (29, 49, 290) and protein
levels (29) were significantly elevated in the distal colon
in response to application of aldosterone. The transepithelial potential and amiloride-sensitive equivalent shortcircuit current in the distal colon are higher in SGK1
knockout animals under both control and low-salt conditions (unpublished observations). Thus SGK1 is apparently not required for stimulation of ENaC in the distal
colon.
In contrast to SGK1-deficient mice, gene-targeted
mice lacking functional SGK3 show decreased glucose
transport even in the absence of glucocorticoid treatment
(279). Similarly, intestinal transport is impaired in the
SGK1/SGK3 double knockout mouse (132). Again, the
observations parallel the in vitro ability of SGK3 to activate the Na⫹-glucose cotransporter SGLT1 in Xenopus
oocytes (93). Moreover, SGK3 can activate KCNQ1-depenPhysiol Rev • VOL
E. Cardiovascular Function
As regulation of blood pressure is a function of salt
balance, the dual effect of SGK1 on both Na⫹ intake and
renal Na⫹ excretion could be expected to influence blood
pressure (Fig. 5). SGK1 expression is indeed enhanced in
kidneys of the salt-sensitive Dahl rat, a well-known model
of salt-sensitive hypertension (106). Moreover, a variant
of the SGK1 gene correlates with enhanced blood pressure (56, 339), as described in more detail below.
The effect of SGK1 on Na⫹ reabsorption and thus
blood pressure may require activation of SGK1 by insulin
(see Fig. 1). Lack of SGK1 in mice has little effect on
blood pressure under either control conditions or after
treatment with excess mineralocorticoids plus excess
salt, consistent with SGK1-independent stimulation of
Na⫹ reabsorption by mineralocorticoids (326). If, however, hyperinsulinemia is induced in the animals, by pretreatment with a high-fructose diet (149) or a high-fat diet
(150), salt excess leads to an increase in blood pressure in
wild-type, but not SGK1-deficient, animals. Presumably,
SGK1 is required for the stimulation of renal Na⫹ retention by insulin, and thus mediates the salt-sensitizing
effect of hyperinsulinism.
Among the tissues with particularly high expression
of SGK1 (349) and SGK3 (172) is the heart. Thus cardiac
ion channels are likely targets for regulation by either
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SGK1 may participate in the regulation of transport
not only in the kidney and gastrointestinal tract, but also
in other epithelia. SGK1 is expressed in lung tissue (360)
and may, at least in theory, participate in the regulation of
ENaC and CFTR in the alveolar epithelium. Along those
lines, glucocorticoids have been shown to stimulate the
expression and activity of ENaC in bronchial epithelial
cells, an effect paralleled by enhanced SGK1 expression
(161). Excessive expression of SGK1 has been observed
in lung fibrosis (360), as described below.
SGK1 is further expressed in cornea (261) and ocular
ciliary epithelium (260) and may thus participate in the
regulation of fluid transport in the eye. In addition, SGK1
could participate in the regulation of transport in the stria
vascularis of the inner ear. Secretion of K⫹-rich fluid in
this epithelium involves KCNE1/KCNQ1, ClC-Ka/barttin,
ClC-Kb/barttin, and Na⫹-K⫹-ATPase (282, 358), all of
which are regulated by SGK1 (see above).
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LANG ET AL.
kinase (Fig. 6). As indicated above, SGK1 stimulates the
activity of SCN5A, Kv4.3, Kv1.5, and KCNE1/KCNQ1, all
channels affecting the shape and duration of the cardiac
action potential (Fig. 6). Genetic defects of SCN5A or
KCNE1/KCNQ1 may underlie long Q-T syndrome (334), a
disorder caused by delayed myocyte repolarization. Presumably SGK1 is not required for maintenance of normal
Q-T but may have the capacity to shorten Q-T. In support
of this, a gene variant of SGK1, presumably conferring
enhanced SGK1 activity (56, 57), is indeed associated with
a shortened Q-T interval in humans (58).
The ability of SGK1 to inhibit the inducible nitric
oxide (NO) synthase (139) could at least in theory bear
considerable impact on the maintenance of blood pressure during inflammatory disease, a possibility not explored yet in any extent.
F. Neuromuscular Function
The ability of the SGKs to upregulate the glutamate
transporters EAAT1 (39), EAAT2 (37), EAAT3 (283),
EAAT4 (43), and EAAT5 (41) points to their potential role
in neuroprotection. The transporters serve to clear glutamate from the synaptic cleft after release (88, 177, 195,
196, 270), and thus terminate synaptic transmission.
Physiol Rev • VOL
In addition, the regulation of Kv channels by the SGK
protein kinases (see above) could participate in regulating the cell membrane potential in neurons (63, 104, 191,
199, 255, 295, 296). Moreover, SGK1 increases the expression of the kainate receptor GluR6, which is important for
synaptic transmission and plasticity in the hippocampus
(54, 76, 77, 154, 225). SGK1 presumably accounts for
cerebral GluR6 upregulation following glucocorticoid
treatment (308). Thus SGK1 could participate in the neuronal effects of glucocorticoids (167, 215), which may
enhance the responsiveness of the brain but may at the
same time favor neurotoxicity (167, 262). SGKs could
further participate in the signaling of brain-derived neurotrophic factor (BDNF) (283), which triggers the PI 3-kinase cascade (8) and could thus be expected to stimulate
the SGK isoforms. BDNF influences neuronal survival,
plasticity, mood, and long-lasting memory formation (48,
220, 223, 377). PI 3-kinase was shown to mediate the
BDNF-dependent spatial memory formation in rats (223).
Several observations point to a role of SGK1 in memory consolidation. SGK1 expression in the hippocampus
is stimulated by fear conditioning (338), elevated plus
maze exposure (175), and after enrichment training (194);
the latter effect was reversed by inhibition of N-methylD-aspartate (NMDA) receptors (194). Transfection of mu-
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⫹
FIG. 6. Regulation of cardiac ion channels by SGK1. Activation of the voltage-gated Na channels SCN5A, the slowly activating delayed rectifier
K⫹ channels KCNE1/KCNQ1, the A-type Kv4.3, and the Na⫹-K⫹-ATPase by SGK1 in heterologous expression systems. A: currents carried by SCN5A,
KCNE1/KCNQ1, Kv4.3/KchIP2b, and Na⫹-K⫹-ATPase, respectively, all without and with coexpression of SGK1. B: calculation of the SGK1-stimulated
currents carried by SCN5A (INa increased by 50%), Kv4.3&KchIP2b (ITo increased by 70%), KCNQ1&KCNE1 (IKs increased by 200%), and the
Na⫹-K⫹-ATPase (increased by 50%) using the Luo-Rudy based ventricular action potential model LabHeart4.7. C: arithmetic means of the Q-T
interval (in ms) in an average population (total) and in individuals carrying the SGK1 gene variant (E8CC/CT-I6CC) leading to increased SGK1
expression. [Data modified from Boehmer et al. (42) (SCN5A), Baltaev et al. (21) (Kv4.3), Embark et al. (100) (KCNE1/KCNQ1), Setiawan et al. (285)
(Na⫹/K⫹-ATPase), and Busjahn et al. (58) (Q-T interval).]
FUNCTIONAL SIGNIFICANCE OF SGK ISOFORMS
G. Other Functions
In C. elegans, lack of SGK1 was followed by defective
egg laying, extended generation time, increased stress
resistance, and extension of life span (142). These observations prompted speculations that SGK1 may similarly
affect life span in mammals (142). Under standard dietary
conditions, however, the life span of SGK1 knockout mice
was similar to that of their wild-type littermates (unpublished observations). This observation does not preclude
a negative effect of SGK1 on human longevity under unfavorable environmental conditions.
A striking phenotype of gene-targeted mice lacking
functional SGK3 is delayed hair growth (214), a defect
presumably due to apoptosis of keratinocytes (9).
H. Phenotype of Gene-Targeted Mice Lacking
SGK1, SGK3, or Both
As indicated above, the phenotype of both SGK1
knockout mice (368) and SGK3 knockout mice (214) is
surprisingly mild. SGK1 mice have no obvious defect
(368), whereas the SGK3 mice display a transient delay of
hair growth and body weight increase (214). Closer analysis reveals the decreased ability of SGK1 knockout mice
to retain salt under a salt-deficient diet (368), or to adequately enhance renal K⫹ output during a K⫹ load (151).
Presumably due to salt depletion, plasma aldosterone
concentration is enhanced (368) and renal Ca2⫹ excretion
is decreased (280). The mice are relatively resistant to the
hypertensive effect of a high-fructose diet (149) or a highPhysiol Rev • VOL
fat diet (150) together with salt excess. In the SGK1
knockout mice, the stimulating effect of mineralocorticoids on salt appetite (326), and the stimulating effect on
intestinal glucose uptake (133), is blunted, and the uptake
of glucose into brain, adipocytes, and skeletal muscle
following a glucose load is decreased (45).
Closer inspection of the SGK3 knockout mice revealed decreased basal intestinal glucose transport (279)
and a subtle decrease of locomotion (189).
The SGK1/SGK3 double-knockout mouse shares the
renal phenotype of the SGK1 knockout mouse and the
hair phenotype of the SGK3 knockout mouse (132).
V. PATHOPHYSIOLOGICAL SIGNIFICANCE OF
THE SERUM- AND GLUCOCORTICOIDINDUCIBLE PROTEIN KINASES
A. Tumor Growth
Downregulation of SGK1 has been observed in prostate cancer (259), ovarian tumors (68), and hepatocellular
carcinoma (72). On the other hand, SGK1 appears to
mediate interleukin (IL)-6-dependent survival of cholangiocarcinoma cells (216). Moreover, the transformation of
intestinal epithelial cells by oncogenic ␤-catenin was followed by increased SGK1 expression (230). Inhibition of
SGK1 expression by silencing RNA increased the toxicity
of chemotherapeutic drugs in those cells (216). SGK1 has
been shown to mediate the glucocorticoid-induced resistance of breast cancer cells to chemotherapy (367). Upregulation and overexpression of SGK1 by glucocorticoids inhibits chemotherapy-induced apoptosis (367).
SGK1 has further been invoked to participate in the glucocorticoid- or colony stimulating factor 1 (CSF1)-induced stimulation of invasiveness, motility, and adhesiveness (313). Accordingly, pharmacological inhibition of
SGK1 with LY294002 significantly blunted the stimulation
of adhesiveness following treatment of breast tumor cells
with dexamethasone or CSF1 (313). SGK1 does not, however, share the ability of PKB/Akt to increase motility of
invasive PTEN-deficient cells (143).
B. Hypertension, Obesity, and the
Metabolic Syndrome
As mentioned above, a certain variant of the SGK1
gene [the combined presence of distinct polymorphisms
in intron 6 (I6CC) and in exon 8 (E8CC/CT)] has been
shown to be associated with moderately enhanced blood
pressure (56, 57). This correlation is presumably due to
enhanced stimulation of ENaC by SGK1 in individuals
carrying this variant. This variant of the SGK1 gene is
common, affecting 3–5% of the Caucasian population (56).
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tant inactive and thus presumably transdominant inhibitory SGK1 in rats impaired spatial learning, fear-conditioning learning, and novel object-recognition learning
(194). SGK1 has also been shown to stimulate dendrite
growth (84). SGK1 transcript levels were significantly
higher in hippocampal tissue from fast-learning rats
than from slow-learning rats (318). Transient transfection
of wild-type SGK1 improved, whereas transfection of
inactive SGK1 deteriorated, the learning abilities of rats
(318), further supporting the view that SGK1 is involved in
learning.
Striatal SGK1 transcript levels are transiently increased by a single dose of the psychostimulant amphetamine (127). Neuronal SGK1 gene transcription is further
upregulated after treatment with the hallucinogenic drug
lysergic acid dimethylamide (LSD) (234), by neuronal injury (159), neuronal excitotoxicity (145), and microgravity (84).
SGK3 is similarly upregulated by fear conditioning
(338) and stimulates the AMPA receptor GluR1 (307).
Along those lines, a subtle decrease of locomotion has
been observed in mice lacking functional SGK3 (189).
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Physiol Rev • VOL
Beyond its effect on blood pressure, SGK1-dependent
renal salt retention could facilitate the development of
edema. Particularly the edema after administration of
PPAR␥ agonists (146) or during nephrotic syndrome (32)
could be due to SGK1-dependent volume retention. In the
edema of liver cirrhosis, however, no upregulation of
SGK1 has been observed (376).
C. Neuronal Disease
SGK isoforms regulate the AMPA (307) and kainate
(308) glutamate receptors. The kinases also upregulate
the glutamate transporters (37–39, 41), which serve to
clear glutamate from the extracellular space. Accordingly,
lack of SGK may blunt the glutamate action but at the
same time decrease glutamate clearance from the synaptic cleft. As glutamate may exert neurotoxic effects (22,
26, 92, 217), altered function or regulation of glutamate
transporters and glutamate receptors may foster neuroexcitotoxicity.
Lack of glutamate transporters has indeed been
shown to promote extracellular glutamate accumulation,
excitotoxicity, and ultimately cell death (269, 312, 340).
Along those lines, loss of EAAT2 function has been reported in amyotrophic lateral sclerosis (ALS) (271), lack
of EAAT4 correlates with loss of Purkinje cells during
ischemia (365), and deranged regulation of glutamate
transporters has been implicated in retinopathy following
glaucoma (52) or diabetic retinopathy (89, 314). In theory,
the development of those disorders could be favored by
impaired SGK1-dependent upregulation of glutamate
transporters.
AMPA receptor activation is of key importance for
ischemic-induced cell death (130, 251, 252). AMPA and
kainate receptors also play a role in ALS (103, 336) and
schizophrenia (98), where changes in GluR2 levels are
observed. GluR3 is involved in the autoimmune disease
Rasmussen’s encephalitis that is characterized by severe
epilepsy, hemiplegia, dementia, and inflammation of the
brain (14, 267). Kainate receptors are thought to be involved in epileptic activity (225, 297). Again, deranged
SGK1-dependent regulation of AMPA or kainate receptors
could theoretically participate in the pathophysiology of
those diseases. The ability of SGK1 to upregulate the
creatine transporter CreaT (291) may similarly be of
pathophysiological significance, as individuals with defective CreaT have been shown to suffer from mental retardation (136, 277).
SGK1 could participate in the detrimental effects of
glucocorticoids during certain cerebral injuries including
stroke, seizure, or hypoglycemia (167, 215, 262). To the
extent that the SGK isoforms participate in the signaling
of BDNF (283), they may further contribute to the signaling of BDNF in several neuropsychiatric disorders (190),
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A further study failed to detect a correlation of the gene
variant with blood pressure in patients with renal failure
(317). In this particular group of patients, other more
potent pathophysiological mechanisms may have overridden the subtle effect of the SGK1 gene variant on blood
pressure. In a further study on more than 4,000 individuals, however, the association of the gene variant with
increased blood pressure has been confirmed (339). Moreover, the latter study revealed a relatively strong correlation between insulinemia and blood pressure in individuals carrying the SGK1 gene variant, suggesting a particular
role of SGK1 in the hypertension paralleling hyperinsulinemia (339). Notably, induction of hyperinsulinemia in
mice by pretreatment with a high-fructose diet (149) sensitizes arterial blood pressure to high-salt intake in wildtype but not SGK1-deficient animals. Thus a high-salt diet
unmasks the fructose-induced SGK1-dependent renal Na⫹
retention, which is only overcome by increase of blood
pressure (“pressure natriuresis,” Fig. 5). As indicated
above, SGK1 is required for the antinatriuretic effect of
insulin. Thus SGK1 mediates the salt-sensitizing effect of
hyperinsulinism on blood pressure.
The outlined SGK1 gene variant may further accelerate intestinal glucose absorption by stimulation of SGLT1
and glucose deposition in peripheral tissues including fat
(see above). Enhanced SGLT1 activity, and subsequently
accelerated intestinal glucose absorption, may lead to
excessive insulin release, fat deposition, a subsequent
decrease of plasma glucose concentration, and triggering
of repeated glucose uptake and thus obesity (120). Conversely, inhibitors of SGLT1 counteract obesity (343), so
there is a possibility that SGK1 may influence body
weight. As a matter of fact, the same variant of the SGK1
gene associated with enhanced blood pressure proved to
be similarly associated with increased body mass index
(93). This observation does suggest that SGK1 participates in the generation of metabolic syndrome or syndrome X, a condition characterized by the coincidence of
essential hypertension, procoagulant state, obesity, insulin resistance, and hyperinsulinemia (268). The condition
is associated with enhanced morbidity and mortality from
cardiovascular disease (160, 210, 238). Metabolic syndrome and Cushing’s syndrome share common attributes
(20), but plasma cortisol levels are not usually elevated in
metabolic syndrome (20). Instead, the disorder may be
caused by inappropriate activity of a downstream signaling element. SGK1 is a signaling molecule downstream of
glucocorticoid receptors. Thus a SGK1 gene variant leading to increased SGK1 activity would trigger glucocorticoid actions without the need for stimulation by enhanced
plasma glucocorticoid concentrations. Needless to say,
additional experimental effort is needed to define the
presumed role of SGK1 in the development of metabolic
syndrome.
FUNCTIONAL SIGNIFICANCE OF SGK ISOFORMS
D. Diseases Involving Fibrosis
SGK1 is expressed in a variety of fibrosing tissues
such as in Crohn’s disease (352), lung fibrosis (360), liver
cirrhosis (110), fibrosing pancreatitis (170), diabetic nephropathy (184), glomerulonephritis (118), and puromycin aminonucleoside-induced experimental rat nephrotic
syndrome (32). SGK1 is upregulated by TGF-␤ (352), a
well-known stimulator of matrix protein deposition in a
variety of fibrosing diseases (169, 174, 286, 385, 387). As
illustrated in Figure 2, SGK1 triggers nuclear translocation of NF␬B (384), which in turn upregulates the expression of connective tissue growth factor (CTGF) (35).
CTGF is a profibrotic factor (51, 115, 157), which participates in the stimulation of matrix protein synthesis and
fibrosis in a variety of diseases (192, 253, 257, 273, 356).
SGK1 has most recently been shown to be required
for the stimulating effect of the mineralocorticoid DOCA
on cardiac CTGF formation, an effect involving activation
of NF␬B (323). Accordingly, SGK1 knockout mice were
protected against the profibrotic effects of DOCA (323).
Physiol Rev • VOL
Moreover, SGK1 potentiates the effect of high glucose
concentrations on renal fibronectin formation (107). The
profibrotic effect of SGK1 is in seeming contrast to the
known anti-inflammatory effect of glucocorticoids, which
stimulate the expression of SGK1. However, the synthetic
glucocorticoid dexamethasone can also enhance the expression of CTGF (82) and collagen (294) and thus contribute to the pathogenesis of certain fibrotic diseases
such as inflammatory bowel disease (82).
E. Ischemia
SGK1 transcription is upregulated by ischemia of the
brain (236) and presumably other tissues. Several effects
of SGK1 could in concert facilitate cellular survival during
energy shortage. For instance, stimulation of creatine
uptake by the Na⫹-coupled creatine transporter CreaT
(291) would enhance the capacity to bind phosphate to
creatine and thus increase the cellular ability to store
rapidly available energy. Stimulation of the glucose transporter GLUT1 (241) would provide the cell with fuel for
anaerobic glycolysis.
In theory, SGK1 may inhibit apoptosis and thus prolong cell survival. On the other hand, energy depletion
compromises the activity of the energy-consuming Na⫹K⫹-ATPase, the subsequent cellular K⫹ loss leads to depolarization, entry of Cl⫺, and thus cell swelling (181).
Cell swelling could eventually disrupt the integrity of the
cell membrane, leading to necrosis, with release of cellular proteins, inflammation, and thus to more severe tissue
injury than apoptosis (180). The stimulation of the Na⫹K⫹-ATPase by SGK1 may prevent cellular K⫹ loss and
thus foster cell survival but at the same time accelerate
the energy depletion.
The stimulation of matrix deposition by SGK1 may
contribute to the replacement of cellular tissue with connective tissue. By this means, energy-consuming cells are
replaced by extracellular matrix and thus energy consumption is cut down. On the other hand, the extracellular matrix cannot maintain tissue-specific cellular function, and thus replacement of cells by matrix eventually
leads to organ failure. To which extent the expression of
SGK1 is beneficial or detrimental for the cells, organs, or
the organism may depend on the affected tissue and the
extent or duration of energy depletion. Clearly, SGK1
participates in the pathophysiology of ischemia, but at
this stage, it cannot be predicted whether inhibition of
SGK1 would blunt or aggravate the sequelae of energy
depletion.
VI. CONCLUSIONS AND PERSPECTIVES
The serum- and glucocorticoid-inducible kinase
SGK1 and its isoforms SGK2 and SGK3 are potent and
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such as schizophrenia (364), depression (319), and Alzheimer’s disease (220). Moreover, BDNF concentrations
are modified after major psychiatric treatment strategies,
i.e., antidepressant, neuroleptic, and electroconvulsive
therapy treatment (219, 274).
The ability of SGK1 to phosphorylate tau (71) may be
of some relevance for the pathophysiology of Alzheimer’s
disease, which is paralleled by hyperphosphorylation of
tau (109). Moreover, transgenic mice overexpressing
TGF-␤ develop Alzheimer’s disease like vascular and
meningeal alterations (122). As indicated above, TGF-␤ is
a strong stimulator of SGK1 expression (352). On the
other hand, TGF-␤ has been postulated to be neuroprotective, counteracting the pathophysiology of Alzheimer’s
disease by decreasing the accumulation of ␤-amyloid peptide (383). The evidence for an involvement of SGK1 in
the pathophysiology of Alzheimer’s disease is presently
circumstantial.
SGK1 has further been shown to phosphorylate huntingtin, thus counteracting huntingtin toxicity (258).
Moreover, genomic upregulation of SGK1 coincides with
the onset of dopaminergic cell death in a model of Parkinson’s disease (163, 304). It is not clear from those latter
studies, however, whether SGK1 protects from or stimulates cell death. Finally, excessive expression of SGK1 has
been observed in Rett syndrome (RTT), a disorder with
severe mental retardation (237).
In summary, compelling evidence suggests a role for
SGKs in the pathophysiology of brain disease. However,
we are presently far from understanding the contribution
of SGKs to the deterioration or maintenance of neuronal
function.
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ACKNOWLEDGMENTS
We are indebted to L. Subasic, T. Loch, and N. Eckberger
for meticulous preparation of the manuscript. We appreciate the
valuable suggestions of Rebecca Lam.
Address for reprint requests and other correspondence:
F. Lang, Dept. of Physiology, Univ. of Tuebingen, Gmelinstrasse 5, 72076 Tuebingen, Germany (e-mail: florian.lang
@uni-tuebingen.de).
GRANTS
We gratefully acknowledge support by Deutsche Forschungsgemeinschaft Grant La 315/4 – 4, Bundesministerium für
Wissenschaft und Forschung IZKF Grant 01KS9602, National
Institute of Diabetes and Digestive and Kidney Diseases Grants
DK-56248 and DK-70667, and American Heart Association Grantin-Aid 655232Y.
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diverse regulators of metabolism, transport, transcription,
and enzyme activity and thus participate in the regulation
of diverse functions such as epithelial transport, excitability, cell proliferation, and apoptosis. The phenotype of
gene-targeted mice lacking SGK1, SGK3, or both is mild,
indicating that the function of those two kinases is not
crucial for basic functions or that it is compensated by the
function of other kinases, such as SGK2 or the PKB/Akt
isoforms. Nevertheless, following appropriate challenges
the lack of SGK1 and SGK3 becomes apparent and physiologically important. Particular evidence points to their
role in electrolyte balance, metabolic syndrome, tumor
growth, neurodegeneration, fibrosing disease, and sequelae of ischemia. It is anticipated that future experiments shall reveal further targets under the control of the
SGK isoforms, further molecular mechanisms involved
and, most importantly, further insight into the physiological and pathophysiological significance of SGK-dependent regulation.
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