Adv Physiol Educ 31: 5–16, 2007;
doi:10.1152/advan.00088.2006.
Staying Current
The membrane and lipids as integral participants in signal transduction: lipid
signal transduction for the non-lipid biochemist
Kathleen M. Eyster
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota
Submitted 24 August 2006; accepted in final form 20 November 2006
use chemical messengers to communicate with each other, and single-celled organisms respond to chemical messengers in their environment.
Moreover, the intracellular compartments and organelles of a
cell must communicate with each other. The chemical messengers used in cellular communication are either water soluble or
lipid soluble. Cells, themselves, are defined by the physical
presence of the lipid bilayer membrane barrier that separates
the inside of a cell from the outside of a cell, and intracellular
compartments are defined by lipid membrane barriers as well.
Extracellular and intracellular water-soluble chemical messengers cannot cross cellular membranes, so their messages must
be transduced across the membrane. Lipid-soluble messengers
can cross cell membranes and communicate directly with the
contents of the cell by binding to intracellular receptors. Signal
transduction is the field of science that seeks to comprehend the
mechanisms that cells have developed to interpret the messages
carried by extra- and intracellular chemicals into messages that
the cell can understand. Thus, the field of signal transduction is
important because of its fundamental role in cellular communication and regulation of cellular responses.
The field of signal transduction is also important because
cellular communication often goes awry in pathological situations. Many diseases result from aberrant communication
among cells or from problems with the machinery of signaling
pathways (6, 27, 28, 54, 67). For example, mutations in
components of signal transduction pathways that regulate mitosis can result in tumorigenesis (6, 34, 46, 89, 90).
Cellular physiology requires the presence of a barrier between cells, but the cell membrane is not merely a barrier that
must be traversed; rather, the membrane and its constituent
lipids are also indispensable participants in many events of
signal transduction. Reviews of signal transduction have often
focused on the cascades of protein kinases and protein phosphatases and their cytoplasmic substrates that become activated
in response to extracellular signals. Lipids, lipid kinases, and
lipid phosphatases have not received the same amount of
attention as proteins in studies of signal transduction. It is
important to not only acknowledge the contribution of the
membrane and lipids to signal transduction but also to recognize that this contribution is substantial. For example, membrane lipids participate as components of signal transduction
pathways and as docking sites for cytoplasmic signaling proteins, and they give rise to cleavage products that act as ligands
or substrates for other signaling molecules. Nonmembrane
lipids have a role in signal transduction as well; lipids serve as
ligands, and posttranslational lipid modifications provide a
means for proteins to associate intimately with the membrane.
The magnitude and diversity of the roles of the membrane and
lipids in signal transduction can be easily overlooked. Therefore, this review focused on the role of the cell membrane and
its constituent lipids in signal transduction.
A look at the big picture sets the stage for a discussion of the
details of lipid signal transduction. The first important aspect of
the big picture is the interrelatedness among the lipid signaling
pathways (Fig. 1). The details of these complex interactions are
described in the following text, but several examples can be
pointed out here. As shown in Fig. 1, phosphatidylcholine is the
parent molecule for a number of lipid messengers. The presence
in a given cell of one phospholipase (PL) enzyme versus another
determines whether a parent lipid molecule such as phosphatidylcholine gives rise to arachidonic acid (AA), phosphatidic acid
(PA), or platelet-activating factor (PAF). The interrelatedness of
lipids involved in signal transduction is further illustrated by the
fact that the polar head group of sphingomyelin, phosphorylcholine, is the same as the polar head group of phosphatidylcholine.
Many other examples of the interrelatedness of lipid signaling
pathways are described in the following text.
The second important aspect of the big picture is the significant amount of interaction among the signal transduction
pathways activated by lipid mediators (Fig. 2). Many of the
Address for reprint requests and other correspondence: K. M. Eyster, Div. of
Basic Biomedical Sciences, Sanford School of Medicine, Univ. of South Dakota,
414 E. Clark St., Vermillion, SD 57069 (e-mail: [email protected])
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
phospholipase; sphingomyelin; ceramide; fatty acid; lysophospholipid; phosphatidylinositol
THE CELLS OF A MULTICELLULAR ORGANISM
1043-4046/07 $8.00 Copyright © 2007 The American Physiological Society
5
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Eyster KM. The membrane and lipids as integral participants in
signal transduction: lipid signal transduction for the non-lipid biochemist. Adv Physiol Educ 31: 5–16, 2007; doi:10.1152/advan.
00088.2006.—Reviews of signal transduction have often focused on the
cascades of protein kinases and protein phosphatases and their cytoplasmic substrates that become activated in response to extracellular signals.
Lipids, lipid kinases, and lipid phosphatases have not received the same
amount of attention as proteins in studies of signal transduction. However, lipids serve a variety of roles in signal transduction. They act as
ligands that activate signal transduction pathways as well as mediators of
signaling pathways, and lipids are the substrates of lipid kinases and lipid
phosphatases. Cell membranes are the source of the lipids involved in
signal transduction, but membranes also constitute lipid barriers that must
be traversed by signal transduction pathways. The purpose of this review
is to explore the magnitude and diversity of the roles of the cell
membrane and lipids in signal transduction and to highlight the interrelatedness of families of lipid mediators in signal transduction.
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LIPID MEDIATORS IN SIGNAL TRANSDUCTION
lipid mediators leave the cells in which they originate and bind
to G protein-coupled receptors (GPCRs) in the membrane of
the same cell or of neighboring cells. Many of the lipid signals
converge on PLC, phosphatidylinositols (PIs), or Ca2⫹ (Fig. 2).
As described in the following text, the interrelatedness and
interconvertibility of many of the lipid mediators contribute to
the complexity of these pathways.
Lipid Components of the Cell Membrane
A discussion of membrane lipids and lipid structures will
facilitate this review of lipid signal transduction and will
clarify the interrelatedness of lipid mediators. At the most
fundamental level, the cell membrane is composed of a lipid
bilayer with polar hydrophilic head groups that face the cytoplasmic and extracellular spaces and hydrophobic tails that
face each other. Integral membrane proteins are embedded in
the lipid bilayer or associated with the membrane by posttranslational attachment of a lipid group to the protein.
Phospholipids comprise the most abundant class of membrane lipids. Phospholipids are composed of two fatty acid
tails, glycerol, a phosphate group, and a polar head group (Fig.
3). Of the phospholipids, phosphatidylethanolamine, phosphatidylserine, and PI are found primarily in the inner leaflet of the
membrane, whereas phosphatidylcholine is found primarily in
the outer leaflet of the membrane. Phospholipids do not flip
flop from one leaflet to the other independently. A class of
enzymes called phospholipid scramblases catalyze the movement of phospholipids from one leaflet to the other (77).
Sphingomyelin and related molecules such as ceramide and
sphingosine make up another class of compound membrane
lipids (Fig. 3). Sphingomyelin is composed of sphingosine, a
fatty acid, a phosphate group, and choline. Ceramide and
sphingosine are released by the sequential cleavage of sphingomyelin. The properties of sphingomyelin molecules allow
them to form hydrogen bonds with each other within the
membrane. Cholesterol is also an important component of the
cell membrane of eukaryotic cells (Fig. 3). In eukaryotic cells,
cholesterol fills the gaps among sphingomyelin molecules. The
result is membrane regions with high concentrations of sphingomyelin and cholesterol called lipid rafts (15, 65, 83). Some
protein components of signal transduction pathways have an
affinity for lipid rafts, whereas others are excluded (15). Extracellular proteins with glycosylphosphatidylinositol (GPI)
anchors and myristoylated or palmitoylated intracellular proteins associate with lipid rafts (65). Transmembrane proteins
also enter lipid rafts, but the mechanisms that regulate the
Fig. 2. The interrelatedness of lipid ligands and intracellular lipid
mediators. Many lipid mediators [prostaglandins (PGF2␣, PGE2,
and PGI2), thromboxane A2 (TXA2), leukotrienes (LTs), S1P, PAF,
LPC, SPC, and lysophosphatidic acid (LPA)] act as ligands at G
protein-coupled receptors (GPCRs), which activate PLC-␤. In turn,
PLC-␤ cleaves the membrane lipid PI(4,5)P2 to release DAG and
IP3. IP3 releases Ca2⫹ from intracellular stores, and Ca2⫹ and DAG
together activate PKC. Growth factors (GFs) activate receptor
protein tyrosine kinases (RPTKs) and the same PI(4,5)P2 breakdown via PLC-␥. GFs also activate PI3K as well as the MAPK
pathway. Ca2⫹ and MAPK together activate cytoplasmic PLA2
(cPLA2) to convert phosphatidylcholine to LPC plus arachidonic
acid (AA). Ca2⫹ and MAPK also activate lysoPAF acetyltransferase (lysoPAF AT) to convert LPC to PAF. MAPK stimulates
sphingosine kinase, which converts sphingosine to S1P. PI(4,5)P2,
PKC, and the small G proteins RalA and ARF6 together activate
PLD to convert phosphatidylcholine to PA. PA activates PI5K as
well as the serine/threonine protein kinase Raf. It can also be
converted to DAG or LPA (dotted lines). PI(3,4,5)P3 forms a
binding site for phosphoinositide-dependent protein kinase 1
(PDK1) and the serine/threonine protein kinase Akt/PKB. PDK1
then phosphorylates Akt/PKB as part of its activation. Factors that
serve as extracellular ligands are shown in italics.
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Fig. 1. The interrelatedness and interconvertibility of the lipid signaling pathways discussed in the text. PLA2, phospholipase A2; PLC, phospholipase C; PLD,
phospholipase D; LPC, lysophosphatidylcholine; COX, cyclooxygenase; LOX, lipoxygenase; CYP2C, cytochrome P-450 2C; HETE, hydroxyeicosatetraenoic
acid; HODE, hydroxyoctadecadienoic acid; HPETE, hydroxyperoxyeicosatetraenoic acid; EETs, eicosatrienoic acids; PAF, platelet-activating factor; PA,
phosphatidic acid; DAG, diacylglycerol; IP3, inositol (1,4,5)-trisphosphate; PI(4)P, phosphatidylinositol (4)-phosphate; PI(4,5)P2, phosphatidylinositol (4,5)bisphosphate; PI(3,4,5)P3, phosphatidylinositol (3,4,5)-trisphosphate; PI5K, phosphatidylinositol 5-kinase; PI3K, phosphatidylinositol 3-kinase; C1P, ceramide1-phosphate; S1P, sphingosine-1-phosphate; SPC, sphingosylphosphorylcholine.
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association of transmembrane proteins with lipid rafts are
poorly understood. There does not appear to be a specific
protein domain that targets transmembrane proteins to lipid
rafts (65). The presence of sphingomyelin and, therefore, lipid
rafts allows sphingomyelin to serve an important structural role
in the cell membrane as well as to participate in signal
transduction pathways.
A fatty acid is composed of a long-chain aliphatic carboxylic
acid. Fatty acids may be saturated (no double bonds in the
hydrocarbon chain), monounsaturated, or polyunsaturated (one
or more double bonds in the hydrocarbon chain, respectively).
The presence of a double bond in a fatty acid adds a kink. Fatty
acids that have more double bonds have more kinks in their
structure and take up more space. Thus, as the number of
double bonds increases, the membrane becomes more fluid
because the fatty acids fit less closely together. Similarly, the
fewer the number of double bonds (saturated fatty acids), the
more tightly the fatty acid tails fit together and the less fluid the
membrane. As shown in Fig. 3, many membrane lipids contain
fatty acid chains. The fatty acid components of membrane
lipids vary widely. Two lipids with the same parent structure
may have very different fatty acids attached even though they
come from the same source or from the same membrane.
Physiologically, this means that hydrolysis of a given species
of membrane lipid may yield different fatty acids. Also, the
identity of a lipid is determined by its parent structure and not
by its fatty acids, since the fatty acids may vary.
Phospholipases
The family of PL enzymes cleaves membrane phospholipids; each of the PLs acts at a different site on the phospholipid
(Fig. 4). Both cell membrane and intracellular membrane
phospholipids are substrates for PLs. The products that result
from these cleavages are involved in a variety of aspects of
signal transduction.
Typically, more is taught and written about PLC than other
phospholipid, so it is the most familiar of all the PL enzymes
involved in signal transduction. PLC cleaves the polar head
phosphate from phospholipids, leaving behind a molecule of
diacylglycerol (DAG). The polar head phosphate is released
into the cytoplasm, whereas DAG with its fatty acid chains
remains an integral component of the membrane (Figs. 4 and
5). In regard to signal transduction, the most important phospholipid target of PLC is PI (4,5)-bisphosphate [PI(4,5)P2]. PIs
comprise only 4 –5% of the total phospholipid content of the
membrane (5) but perform a variety of roles in signal transduction (17).
Two isoforms of PLC are activated in response to extracellular ligands. The ␤-isoform of PLC (PLC-␤) is activated via
ligand stimulation of GPCRs and Gq isoforms of heterotrimeric
G proteins (57) (Fig. 5A). Examples of ligands that activate
PLC-␤ via GPCR/Gq include prostaglandin (PG)F2␣, PGE2
(via the EP3D receptor), prostacyclin, and thromboxane (55). In
contrast, stimulation of the ␥-isoform of PLC (PLC-␥) is
achieved by ligand-activated enzyme-linked tyrosine kinase
receptors (7) (Fig. 5A). Examples of ligands that activate
PLC-␥ via enzyme-linked tyrosine kinase receptors include
EGF, PDGF, FGF, and NGF (7). Two second messengers are
released by the PLC cleavage reaction. The polar PI head
group [PI (1,4,5)-trisphosphate (IP3)] that is liberated upon
cleavage by PLC is released into the cytoplasm, where it acts
as a second messenger (Fig. 5). IP3 releases Ca2⫹ from intracellular stores (4) (Fig. 2). Ca2⫹, in turn, activates its own
series of signaling functions (78), including the activation of
cytoplasmic PLA2 (cPLA2) (8). DAG is the additional second
messenger. DAG was the first membrane lipid to be identified
as a direct component of a signal transduction pathway (39).
The first of the cellular messenger functions of DAG to be
identified was the activation of the conventional (␣, ␤I, ␤II,
and ␥) and novel (⑀, ␩, ␦, and ␪) isoforms of PKC (50) (the
atypical isoforms of PKC, PKC-␫ and -␰, are not activated by
DAG). In addition, DAG activates chimaerins, proteins with
GTPase-activating protein activity toward Rac (87). DAG
functions are confined to the lipid bilayer (Fig. 5A). Interestingly, the conventional and novel isoforms of PKC bind to the
membrane phospholipid phosphatidylserine as well as to DAG
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Fig. 3. Membrane lipid structures. A: structure of a phospholipid (specifically, phosphatidylinositol). B: structure of sphingomyelin. C: structure of ceramide.
D: structure of cholesterol. Fatty acids in the lipids are designated “R” and are shown in red. Fatty chains attached to the lipids are shown in blue. The structures
are oriented with the hydrophobic regions toward the top and with the polar head groups toward the bottom.
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LIPID MEDIATORS IN SIGNAL TRANSDUCTION
to achieve activation (82). Since DAG and phosphatidylserine
are confined to the membrane, the conventional and novel
isoforms of PKC must translocate to the membrane for activation.
The body of literature describing the family of PLD isoforms
is much smaller than that for PLC. The two isoforms of PLD
(PLD1 and PLD2) are both palmitoylated as a posttranslational
modification and both contain pleckstrin homology (PH) and
phox homology (PX) lipid binding domains. The palmitoylation and two lipid binding domains all contribute to the
association of PLD isoforms with membrane lipids (21). PLD
cleaves the polar head group from phospholipids, leaving PA
behind. Thus, PA is composed of the fatty acid chains, glycerol, and phosphate group of the initial phospholipid (Fig. 4).
Activation of PLD1 requires association with a complex of
proteins and lipids. These include two of the small GTPases,
RalA and ARF6, the conventional PKC isoform PKC-␣, and
the membrane phospholipid PI(4,5)P2 (introduced above as the
substrate for PLC) (25) (Figs. 2 and 6). PLD does not appear
to be directly associated with a receptor; that is, PLD is not
activated by a GPCR/G protein or by an enzyme-activated
receptor as are the PLC isoforms described above. Rather, PLD
isoforms are activated by downstream effectors of other signaling pathways. The activation of PKC by PLC-␤ or PLC-␥,
as described above, and activation of guanine nucleotide exchange factors that activate RalA and ARF6 result in the
activation of PLD (36). Therefore, PLD responds to activation
by extracellular ligands, but the response is more indirect than
direct.
The most important substrate for PLD in regard to signal
transduction is phosphatidylcholine, which yields PA and choline upon cleavage by PLD (25) (Figs. 1, 4, and 6). PA is a lipid
mediator of PLD and carries out specific signal transduction
functions, whereas choline has not been shown to have signaling properties. One function of PA is to activate the enzyme PI
4-phosphate 5-kinase (PI5K), which is responsible for the
phosphorylation of PI 4-phosphate to yield PI(4,5)P2 (25).
Thus, the PLD1-PA pathway is involved in the synthesis of
PI(4,5)P2, which is the substrate for the PLC pathway. Also,
because PI(4,5)P2 is required for the activation of PLD1,
synthesis of PI(4,5)P2 can be considered a positive feedback
step in maintaining the activation of PLD1 (Fig. 2). PA is also
involved in the activation of the serine/threonine protein kinases Raf and mammalian target of rapamycin (25). In addition, PA and DAG are interconvertible. PA can be converted to
DAG by phosphatidic acid phosphohydrolase and back by
DAG kinase (Figs. 1 and 4). DAG has its own set of signaling
functions, as described above.
The PLA2 family is much larger than the PLC or PLD
families, with multiple forms of both cytosolic and secretory
isoforms (53). Secretory PLA2 (sPLA2) isoforms are stored in
secretory granules and secreted in response to stimuli (53).
sPLA2 isoforms are activated by Ca2⫹. Since the levels of
Ca2⫹ in the extracellular space are high enough to maintain the
activity of sPLA2, the actual regulation must occur at the points
of gene transcription (regulation of availability of the gene
product) and of protein secretion. Factors that increase the
transcription and secretion of sPLA2 include inflammatory
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Fig. 4. Cleavage products of the action of phospholipases on phospholipids. The specific parent phospholipid shown here is phosphatidylcholine. R1 and R2, fatty
acids; DAGK, DAG kinase; PAP, phosphatidic acid phosphohydrolase.
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Fig. 6. Regulation of PLD1. A complex of proteins and lipids must form at
the cytoplasmic face of the membrane to activate PLD1 (green). PLD1
associates with the membrane through palmitoylation as well as through its
pleckstrin homology and phox homology domains. PKC-␣ (purple) is
activated by its interaction with the membrane lipid DAG (orange). The
two small G proteins, ARF6 and RalA (brown), must be activated by GTP
(gold). PI(4,5)P2 must also be present (red). In the presence of PI(4,5)P2,
active PKC-␣, and active ARF6 and RalA, PLD1 cleaves the membrane
phospholipid phosphatidylcholine (blue) to yield choline and PA. The polar
head group, choline, is released to the cytoplasm. PA remains associated
with the membrane.
mediators such as TNF-␣ and IL-1␤ and downstream mediators of the 12/15-lipoxygenase (LOX) pathway such as 12(S)or 15(S)-hydroxyeicosatetraenoic acid (HETE) and 12(S)-hydroxyoctadecadienoic acid (HODE) (44). cPLA2 isoforms are
activated by increases in intracellular Ca2⫹ and by phosphorylation by several MAPKs (48). Therefore, an increase in
intracellular Ca2⫹ by activation of the PLC-IP3 pathway to
release intracellular Ca2⫹ (Fig. 2) or by opening membrane
Ca2⫹ channels to allow Ca2⫹ entry from the extracellular space
activates cPLA2. Also, activation of the MAPK pathway by
growth factors (such as EGF, PDGF, FGF, and NGF) (7)
activates cPLA2 through phosphorylation by MAPK. Moreover, the literature indicates that multiple levels of interaction
exist among the various isoforms of PLA2 in both regulation
and function. For example, the activation of cPLA2 increases
the concentrations of HETE and HODE, which stimulate the
transcription of sPLA2 (44), and cPLA2 and sPLA2 interact in
the cleavage of lipids (8).
All of the isoforms of PLA2 cleave membrane phospholipids
to yield one free fatty acid plus lysophospholipid (Fig. 4). The
most physiologically important substrate for PLA2 is phosphatidylcholine (Figs. 1 and 7). The fatty acids that are incorporated into phosphatidylcholine vary, but the most common
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Fig. 5. Regulation of PI(4,5)P2 by PLC and
PI(4,5)P2 structures. A: membrane events in
the regulation of PI(4,5)P2 by PLC. On the
left, a ligand (L)-activated GPCR interacts
with a heterotrimeric G protein (G␣q) to activate PLC-␤. On the right, a ligand-activated
RPTK activates PLC-␥. PLC-␤ and PLC-␥
carry out the same reaction (black arrows):
the cleavage of PI(4,5)P2 to yield DAG and
IP3 (red structures). The phosphorylated polar
head group, IP3, is released into the cytoplasm, whereas DAG remains an integral
component of the membrane. B: detailed
structures of PI(4,5)P2 (middle). To the right
are the cleavage products from the action of
PLC on PI(4,5)P2: DAG (blue) and IP3 (red).
To the left is the structure of PI(3,4,5)P3 that
results from the phosphorylation of PI(4,5)P2
by PI3K. The phosphate group added by
PI3K is shown in red.
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The action of PLD plus PLA2 on a phospholipid yields
lysophosphatidic acid (LPA; Fig. 4), which acts as an extracellular ligand by binding to specific edg/LPA GPCRs (42).
LPA stimulates the activity of PLC-␤, PLD, PLA2, the small
GTPase Rho, and the nonreceptor protein tyrosine kinase Src
(23). Diverse roles have been ascribed to LPA, including cell
proliferation, survival, and invasion (23).
Platelet-Activating Factor
and most physiologically important fatty acid that can be
released from phosphatidylcholine by PLA2 is AA (eicosatetraenoic acid) (53). The resulting lysophospholipid is lysophosphatidylcholine (LPC) (69). LPC binds as a ligand at specific
GPCRs (33) and activates PLC-␤ to release IP3 and DAG, with
resultant increases in intracellular Ca2⫹ and activation of PKC
(91) (Fig. 2). In addition, LPC regulates MAPK in a cell
type-dependent manner (91). The activation of MAPK by LPC
occurs by a link between the GPCR and phosphatidylinositol
3-kinase (PI3K) (93). The GPCR for LPC is found at highest
levels in the spleen and thymus, so it is considered to play an
important role in immune system regulation (94). AA released
by PLA2 is the substrate for three different pathways: the
cyclooxygenase (COX), LOX, and cytochrome P-450 2C
(CYP2C) pathways (Figs. 1, 2, and 7). The two isoforms of
COX (COX1 and COX2) give rise to PGs (27, 56, 66). The
COX1 isoform is constitutively expressed, whereas the COX2
isoform is induced by extracellular ligands. Each of the PGs
has its own cell type-specific effects. The isoforms of LOX (5-,
12-, and 15-LOX) give rise to leukotrienes, HETE, HODE,
hydroxyperoxyeicosatetraenoic acids, and lipoxins (67). The
CYP2C pathway gives rise to epoxyeicosatrienoic acids
(EETs) (35). EETs are metabolized to dihydroxyepoxyeicosatrienoic acid (DHETE) by soluble epoxide hydrolase. Each of
these pathways yields multiple products, some of which act as
intracellular messengers (47, 94) and others that leave the cell
and act as ligands on G protein-coupled membrane receptors
(26, 55, 94). The array of specific synthase enzymes for each of
the PGs and leukotrienes that is present in a given cell varies
and determines which PGs or leukotrienes are produced in that
cell. These lipid messengers are involved in a variety of
physiological and pathological processes. For example, PGs are
involved in ovulation (20), gastrointestinal tract function (86), and
inflammation (94) among other functions. Leukotrienes are involved in the respiratory tract, and their overactivation is implicated in asthma (67). EETs have vasodilatory effects, whereas
their metabolites, DHETEs, are vasoconstrictive (79).
Lipid Kinases and Phosphatases
The focus in signal transduction, both in teaching and
experimental design, is usually on protein kinases and protein
phosphatases. As the understanding of lipid signaling molecules expands, the functions of lipid kinases and lipid phosphatases are proving to be equally important to those of
proteins. The PI3K pathway is the most thoroughly studied of
the lipid phosphorylation pathways. PI3K is a downstream
effector of mitogens (90). Mutations of this pathway that result
in unregulated activation have been implicated in cancer (90);
hence, the broad interest in the PI3K pathway. Under normal
circumstances, PI3K is activated by extracellular ligands such
as insulin (19, 72) and other mitogenic growth factors (90)
(Fig. 2). The parent substrate for PI3K is PI, the same phospholipid that is the substrate for the PLC and PLD pathways.
There are many isoforms of PI3K; some of them prefer
PI(4,5)P2 as a substrate to yield PI (3,4,5)-trisphosphate
[PI(3,4,5)P3] as the end product (Figs. 5B and 8) (84). Other
isoforms of PI3K prefer PI as substrate to yield PI (3)monophosphate [PI(3)P] as the end product (84). Both PI(3)P
and PI(3,4,5)P3 act as docking sites for proteins that translocate
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Fig. 7. AA, released by the action of PLA2 on phosphatidylcholine, is the
parent molecule for a variety of lipid mediators. The action of COX on AA
yields the PG family of mediators. The action of CYP2C on AA gives rise to
EET. EET is metabolized to dihydroxyepoxyeicosatrienoic acid (DHETE) by
soluble epoxide hydrolase (sEH). The LOX isoenzymes give rise to LTs,
HETE, HPETE, and lipoxins. lysoPAF AT converts LPC, also released by the
action of PLA2 on phosphatidylcholine, into PAF.
PAF is a modified phospholipid whose potent biological
activities have been recognized for several decades (68). PAF
is derived from the membrane phospholipid phosphatidylcholine. cPLA2 cleaves one fatty acid from phosphatidylcholine to
yield LPC. Acetyl-CoA:lysoPAF acetyltransferase (lysoPAF
AT) then acetylates LPC to yield PAF (61) (Figs. 4 and 7).
Both cPLA2 and lysoPAF AT are activated by Ca2⫹ and via
phosphorylation by MAPK family members such as ERK1,
ERK2, and p38. However, specific MAPKs are responsible for
phosphorylating the two enzymes in different cellular responses. For example, ERK1/2 phosphorylates cPLA2,
whereas p38 MAPK phosphorylates lysoPAF AT (61). In
cellular stress responses, p38 MAPK activates both enzymes in
the PAF synthetic pathway (61). PAF can be found in the
circulation, but data have suggested that the PAF that remains
associated with the membrane of the cell of synthesis is the
more bioactive fraction. Membrane-associated PAF acts in a
paracrine manner at GPCRs on neighboring cells (12, 68).
Receptor binding by PAF activates PLC and cPLA2. The result
of PLC activation is a downstream increase in intracellular
Ca2⫹ and the activation of PKC (Fig. 4). The result of PLA2
activation is increased substrate for the COX, LOX, and
CYP2C pathways as well as for the PAF pathway (Fig. 7). The
result is a positive feedback effect in that the increased intracellular Ca2⫹ contributes to the activation of both cPLA2 and
lysoPAF AT. This enzyme activation coupled with increased
substrate results in greater PAF synthesis (Fig. 2). The functions of PAF include inflammatory responses, stress responses,
ovulation, and blastocyst implantation (12, 61, 68).
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to the plasma membrane (Fig. 8). Proteins with FYVE or PX
domains (named for the first four proteins identified with the
domain: Fab1, YOTB, Vac1p, and EEA) (18, 45) bind to
PI(3)P. PI(3,4,5)P3 serves as the binding site for proteins
containing PH domains [such as Akt/PKB, phosphoinositidedependent protein kinase 1 (PDK1), Btk family tyrosine kinases, and PLC-␥] (17, 45, 70). Thus, the activity of PI3K
results in the formation of binding sites for proteins at the
intracellular face of the plasma membrane (Fig. 8).
A variety of protein kinases are activated after their binding
to PI(3,4,5)P3. For example, Akt/PKB and PDK1 bind to
PI(3,4,5)P3 at the cytoplasmic face of the membrane through
their PH domains. Binding of these two enzymes to membrane
lipids brings them into juxtaposition with each other such that
PDK1 phosphorylates Akt/PKB in its activation loop (58, 74)
(Fig. 8). Akt/PKB is then phosphorylated on a second site by
PDK2. The dually phosphorylated Akt/PKB then dissociates
from PI(3,4,5)P3 and carries out its function of phosphorylating
cellular proteins.
The family of isoforms of Ca2⫹- and lipid-dependent protein
kinase (PKC) also requires phosphorylation of the activation
loop by PDK1 while bound to PI(3,4,5)P3 (58). However,
phosphorylation of PKC in the activation loop is a maturational
step rather than a direct activator of the enzyme. After proteins
are synthesized in the cell, they must undergo processing
before they are mature and can carry out their cellular functions. During maturation, PKC isoforms translocate to the cell
membrane and bind to PI(3,4,5)P3. This brings them into
juxtaposition with PDK1, which phosphorylates PKC in the
activation loop. The conventional and novel isoforms of PKC
must be phosphorylated in this manner before they can be
activated by binding to Ca2⫹ and/or lipids (11, 58). The
atypical isoforms of PKC also undergo phosphorylation in the
activation loop while bound to PI(3,4,5)P3. However, the
subsequent activational steps for atypical PKC isoforms remain
obscure. Some evidence has suggested that phosphorylation of
atypical PKC isoforms (PKC-␫ and PKC-␰) (50) by PDK1 is
sufficient for activation (14, 58), whereas other data have
suggested that activation involves the PB1 protein-protein
interacting domain (32, 62, 95). Thus, PI(3,4,5)P3 is critical for
the maturation and activation of cytoplasmic serine/threonine
protein kinases through both direct (Akt/PKB) and indirect
(PKC) models.
In the same manner that protein phosphatases are critical to
balance the function of protein kinases (22), lipid phosphatases
are critical to balance the function of lipid kinases. For example, phosphatase and tensin homolog deleted on chromosome
10 is a lipid phosphatase that dephosphorylates the three
position of PI(3,4,5)P3 (46, 89) and thereby reverses the lipid
phosphorylation step of PI3K on PI(3,4,5)P3. Myotubularin
dephosphorylates the three position of PI(3)P (89), and the five
position of PI(3,4,5)P3 is dephosphorylated by Src homology
domain 2 (SH2)-containing inositol phosphatase-1 and -2 (6).
Sphingomyelin, Ceramide, and Lipid Rafts
Sphingomyelin is an important structural component of the
cell membrane and of lipid rafts. Sphingomyelin serves an
important functional role as well, as it is the parent compound
of several lipid mediators (15) (Fig. 9). The family of sphingomyelinase isoforms cleaves sphingomyelin to yield ceramide
and phosphorylcholine (16). There are at least five isoforms of
acidic, neutral, and basic sphingomyelinases. The pH designation refers to the optimal pH for association of the substrate
with the enzyme rather than the pH for optimal activity of the
enzyme (41). Despite extensive studies, details of the location
and physiological regulation of sphingomyelinase isoforms
have remained incomplete (49). An example of the complexity
of lipid signaling is illustrated by our present knowledge about
the differential regulation of sphingomyelinase isoforms by
TNF. The binding of TNF to its 55-kDa receptor results in the
stimulation of inflammatory pathways if neutral sphingomyelinase is activated but results instead in apoptosis if acidic
sphingomyelinase is activated (40, 71). In both cases, the
mechanism of action is release of ceramide from sphingomyelin. Because ceramide is extremely hydrophobic, it remains in
the membrane compartment in which it is formed. Neutral and
acidic sphingomyelinases are in separate membrane compartments, so the ceramide they produce stays in those separate
compartments. This compartmentalization isolates the inflammatory pathway from the apoptosis pathway. Signaling by Fas
ligand also activates sphingomyelinase activity and leads to
apoptosis (41).
Similarly to sphingomyelin, ceramide serves both membrane
structural roles as well as signal transduction roles. Structurally, ceramide molecules coalesce to form microdomains
within the lipid rafts. Thus, the action of sphingomyelinase
within the lipid raft gives rise to ceramide microdomains.
Proteins with an affinity for lipid rafts or for ceramide are
brought into juxtaposition with other components of their
respective pathways within the lipid rafts (15). Ceramide
serves as a lipid mediator in its own right and also gives rise to
other lipid mediators. Ceramide can be phosphorylated by the
lipid kinase ceramide kinase (2) to yield ceramide-1-phosphate
(C1P; Fig. 9). The regulation of ceramide kinase has not been
well defined, although data have suggested that its activity
increases in response to Ca2⫹ (2). Alternatively, ceramide can
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Fig. 8. Activation of the protein kinases PDK1 and Akt/PKB by PI3K. In the
absence of stimulation, the protein kinases Akt/PKB and PDK1 are found in
the cytoplasm (left). When the lipid kinase PI3K is activated, it phosphorylates
PI(4,5)P2 (blue) at the three position to form PI(3,4,5)P3 (red). Akt/PKB and
PDK1 translocate to the membrane to bind to the newly formed PI(3,4,5)P3
(right). Binding of the protein PDK1 to the lipid PI(3,4,5)P3 activates PDK1.
The juxtaposition of Akt/PKB and PDK1 that occurs when they bind to
adjacent molecules of PI(4,5)P2 allows PDK1 to phosphorylate Akt/PKB. The
phosphorylation of Akt/PKB activates its kinase activity.
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LIPID MEDIATORS IN SIGNAL TRANSDUCTION
be converted to sphingosine by ceramidase. The regulation of
ceramidase has not been well characterized (73). Sphingosine
kinase, another lipid kinase, then phosphorylates sphingosine
to form sphingosine-1-phosphate (S1P; Fig. 9) (33). Sphingosine kinase is partially activated by the ERK family of
MAPKs, although additional but unidentified factors also appear to be involved in its activation (2).
Ceramide, C1P, sphingosine, and S1P have all been shown
to carry out second messenger functions. Ceramide can directly
activate PKC-⑀ (38) and other signaling pathway components
(30, 40, 71), although the mechanisms of activation have
remained in question, whereas sphingosine can inhibit PKC
(29). Ceramide is a direct activator of type 1 and 2A protein
phosphatases (9), whereas C1P is a potent inhibitor of these
serine/threonine protein phosphatases (10). Both ceramide and
sphingosine stimulate cell cycle arrest and apoptosis (10). In
contrast, both C1P and S1P stimulate cell survival and proliferation and are antiapoptotic (10). Both C1P and S1P are
involved in inflammatory reactions but at different points. S1P
induces the transcription of COX2, whereas C1P activates
cPLA2 to release AA, the substrate for COX2 (2, 10). C1P
appears to have only intracellular messenger functions,
whereas S1P has intracellular messenger functions and can also
be released from the cell and bind to G protein-linked edg/S1P
receptors (42, 43). As an intracellular messenger, S1P has been
proposed to release intracellular Ca2⫹ in a manner similar to
but independent of IP3 (2) (Fig. 2). Since ceramide, C1P,
sphingosine, and S1P are interconvertible, the specific array of
lipid mediators in this pathway in a given cell depends on
which enzymes are available and have been activated in that
cell. The biological effects of these lipid mediators are still
under investigation, and it is expected that other cellular targets
remain to be discovered.
In an alternative pathway, sphingomyelin deacylase converts
sphingomyelin to sphingosylphosphorylcholine (Fig. 9) (51).
Sphingosylphosphorylcholine has intracellular messenger
functions and can also leave the cell to bind to GPCRs (42, 51)
(Fig. 2). Sphingosylphosphorylcholine increases the intracellular concentration of Ca2⫹, activates ERK, and inhibits cell
proliferation (51).
Within the sphingomyelin family of lipid mediators, the
reactions are reversible and the lipids are interconvertible. The
discussion above focuses on the breakdown of a parent lipid to
a product lipid that carries out a specific function as is most
likely to occur in a rapid signal transduction event. However,
the reverse reactions are utilized in the de novo synthesis of the
lipids. For example, the de novo synthesis of sphingomyelin
proceeds from sphingosine through ceramide to sphingomyelin. An increase of ceramide in a lipid raft may come from
sphingomyelin or sphingosine.
Fatty Acids
Fatty acids are integral structural elements of many of the
lipids that have been discussed herein including phospholipids,
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Fig. 9. The sphingomyelin pathway. A: structures of sphingomyelin and its metabolites. B: structures released from sphingomyelin by enzymatic cleavage.
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Role of Dietary Lipids in Signal Transduction
The fatty acids that become incorporated into membrane
lipids can come from the diet or can be synthesized by cells. A
very interesting current topic in both the lay and scientific press
is the role of dietary lipids in health and disease. Saturated fatty
acids include palmitic and stearic acids (80) and are found in
coconut oil, butter, and red meat. Monounsaturated fatty acids
include palmitic and oleic acids (80) and are found in olive and
peanut oils. Polyunsaturated fatty acids are categorized as ␻-6
(linoleic, ␥-linolenic, and AA) or ␻-3 (␣-linolenic, eicosapentaenoic, and docosahexaenoic acid). The ␻ designation refers
to the location of the first double bond in the hydrocarbon chain
relative to the methyl end of the molecule (i.e., the sixth carbon
or third carbon) (92). The ␻-6 polyunsaturated fatty acids are
found in many plant oils such as olive, canola, soybean, corn,
cottonseed, sunflower, and palm. The primary source of longchain ␻-3 polyunsaturated fatty acids is fatty fish (3, 80) such
as salmon and tuna. The sources of saturated and ␻-6 polyunsaturated fatty acids are more common in Western diets than
those of ␻-3 fatty acids. A large body of evidence supports the
concept of healthy effects of polyunsaturated ␻-3 fatty acids
such as those found in fatty fish (28, 60). When ␻-3 fatty acids
are included in the diet, those fatty acids are involved in
cellular functions in competition with the more common ␻-6
fatty acids because the same enzymes are used for the processing of ␻-3 and ␻-6 fatty acids. The ␻-3 fatty acids can
participate in the structures (i.e., membrane lipids) and functions (i.e., signal transduction) described in this review for fatty
acids in general, but the structural differences of ␻-3 and ␻-6
fatty acids result in functional differences as well. The ␻-3
fatty acids are released into the cell when membrane lipids
containing them are cleaved by enzymes such as PLA2 or
sphingomyelin deacylase. The ␻-3 fatty acids are poorer substrates for COX, LOX, and CYP2C enzymes than are ␻-6 fatty
acids such as AA (37). Since COX and LOX mediate inflammatory pathways, the reduced efficiency of these enzymes with
␻-3 fatty acids as substrates allows ␻-3 fatty acids to have an
anti-inflammatory effect when they have been incorporated
into cell membranes (37). As mentioned above, fatty acids
have been shown to act as ligands at both intracellular (37, 47,
94) and membrane receptors (43) and can increase the concentration of ceramide in cell membranes (31, 41). Whether the
ability of ␻-3 fatty acids to regulate the activity of these
pathways differs from that of ␻-6 fatty acids has not been
thoroughly examined, but it is expected that their effects will
differ. The ␻-3 fatty acids also change the composition of the
lipid rafts and the fluidity of the membranes into which they are
incorporated (37). Signal transduction proteins that typically
associate with lipid rafts may be excluded when the content of
␻-3 fatty acids is increased because ␻-3 fatty acids make the
lipid rafts thicker or because the lipid environment is more
unsaturated than when ␻-6 fatty acids are high (37). Lipidanchored proteins may no longer associate with the lipid raft if
the lipid attachment is an ␻-3 fatty acid instead of an ␻-6 fatty
acid. For example, the nonreceptor tyrosine kinase Fyn may be
unable to associate with lipid rafts when it is anchored with a
␻-3 fatty acid instead of an ␻-6 fatty acid (37). Thus, many
mechanisms by which dietary polyunsaturated fatty acids may
affect signal transduction have been proposed. However, the
specific mechanisms involved have not yet been rigorously
demonstrated.
Lipids as Ligands
The above discussion describes specific lipid mediators that
leave the cells of origin and bind to GPCRs in the membranes
of neighboring cells or on the cell of origin. These lipid
mediators include PGs, leukotrienes, lysophospholipids, sphingosylphosphorylcholine, and PAF (42) (Fig. 2). Another class
of lipid-soluble ligands acts as conventional hormones; they
travel in the blood to distant sites, where they bind to receptors
and carry out their biological activity. The steroid hormones
estradiol, progesterone, testosterone, aldosterone, and cortisol
are all derived from cholesterol. 1,25-Dihydroxyvitamin D3
(cholecalciferol) is not a vitamin at all; rather, it too is a
hormone derived from cholesterol. In contrast, the thyroid
hormones triiodothyronine and tetraiodothyronine are synthesized from the amino acid tyrosine; the biosynthesis of the
hormones from tyrosine renders them lipid soluble. These
lipid-soluble ligands bind to intracellular receptors in the steroid receptor superfamily. This family of receptors is much
larger than the number of ligands known to bind to them (1).
Receptors for which no ligands have yet been identified are
called orphan receptors. For example, peroxisome proliferatoractivated receptors (PPARs) were previously considered as
orphan receptors of the steroid receptor superfamily. PPAR-␥
was identified as the binding site for the thiazolidinedione class
of insulin sensitizers (54) before the endogenous ligands for the
receptor were identified. It is now recognized that a variety of
lipids/lipid-derived ligands bind to orphan receptors as in the
case of PPAR. For example, derivatives of androgens are
ligands for the constitutive androstane receptor (24, 76). Fatty
acids are ligands for all isoforms of PPAR (37, 47, 94), and
PGs have been proposed as ligands for PPARs as well (37, 47,
94). Fatty acids have been proposed as ligands at hepatic
nuclear factor-4 and retinoic acid X receptors and as antagonists of the liver X receptor, but the supporting data have not
been conclusive (37).
The classical mechanism of action of ligands bound to the
steroid superfamily of receptors is to modify DNA transcription of specific genes. The ligand/receptor complex dimerizes
and binds to DNA as a transcription factor (1). This is called
the genomic mechanism of action and takes time to develop.
The steps involved include DNA transcription to mRNA,
processing of mRNA, movement of mRNA into the cytoplasm,
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sphingomyelin, ceramide, lysophospholipids, DAG, phosphatidic acid, LPA, PAF, C1P, and sphingosylphosphorylcholine
(Figs. 3, 4, and 9). Fatty acids can be released from these lipids
by PLA2 and other deacylases. In the past, the focus of
signaling research has typically been on the parent compounds
rather than on the fatty acids. However, the focus has been
shifting to include fatty acids as we learn more about the
functions of fatty acids beyond their role in energy metabolism.
Fatty acids have been identified as ligands for members of the
steroid superfamily of intracellular receptors (37, 47, 94) as
well as for membrane GPCRs (43). Fatty acids have also been
implicated in the accumulation of ceramide by stimulating de
novo synthesis (31) or by increasing neutral sphingomyelinase
activity (41). The role of AA as a precursor for multiple lipid
mediators is another fatty acid function that is important in
signal transduction. It is likely that additional functions of fatty
acids in signal transduction have yet to be discovered.
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Lipid-Modified Proteins in Signal Transduction
Many of the components of signal transduction pathways are
modified posttranslationally by the addition of lipid moieties.
For example, ␣-subunits of heterotrimeric G proteins may be
myristoylated or palmitoylated (57) and ␥-subunits of heterotrimeric G proteins are prenylated (57). Small G proteins such
as the Ras, Rab, and Rho/Rac/Cdc42 families undergo palmitoylation, farnesylation, or geranylgeranylation (81), and nonreceptor tyrosine kinases of the Src family may be myristoylated or palmitoylated (52). Palmitoylation of signaling proteins may be reversible such that the protein undergoes cycles
of lipid attachment and disattachment with concomitant cyclic
association with the membrane when attached to the lipid. Gs␣
is an example of a protein that undergoes reversible palmitoylation (52).
Extracellular ligands for membrane receptors may also bear
lipid modifications. For example, ligands for two of the more
recently described pathways, Hedgehog and Wnt, are both
palmitoylated (34, 59). In addition, Hedgehog enjoys the distinction of being the only known protein to which a cholesterol
group is attached (34). Other extracellular proteins are held in
association with the membrane through GPI-anchoring tails.
GPI-anchored proteins are involved in signal transduction and
associate with lipid rafts (75). Examples of GPI-anchored
proteins involved in signal transduction include PH-20 and
GFR␣1. PH-20 is a multifunctional protein found in mammalian sperm membranes (13). The signaling function of PH-20,
an increase in intracellular Ca2⫹ levels, is activated by hyaluronic acid (13). The GPI-anchored protein GFR␣1 is a coreceptor with the receptor tyrosine kinase Ret. In the absence of
the ligand, glial-derived neurotrophic factor (GDNF), GFR␣1
is associated with the lipid raft. Ret cannot associate with the
lipid raft by itself but needs to do so to achieve efficient
tyrosine kinase signaling. In the presence of GDNF, GFR␣1
recruits Ret to the lipid raft so that it is active (83).
Themes in Lipid-Mediated Signal Transduction
As indicated at the beginning of this review, the cell membrane is a structural barrier that is necessary to cell function,
but it has important physiological roles in signal transduction
as well. The field of lipid signal transduction has received only
a fraction of the attention of that of protein signal transduction,
and there are many unanswered questions in this field. Several
themes have emerged in this discussion of lipid mediators in
signal transduction. The first theme is the relatedness and,
often, the interconvertibility of families of lipid mediators (Fig.
1). A second common theme is the relatedness of lipids that act
as ligands and the signal transduction pathways that utilize
lipid mediators. Lipid mediators that leave the cell of origin
and bind to GPCRs in the cell membrane of the same or
neighboring cells include PGs (PGF2␣, PGE2, prostacyclin, and
thromboxane), S1P, PAF, LPC, sphingosylphosphorylcholine,
and LPA (Fig. 2). Most of these GPCRs are linked to PLC-␤,
so they stimulate a lipid-mediated signaling pathway within the
cell that leads to increased activity of PKC and to increased
concentration of intracellular Ca2⫹. The central role of Ca2⫹ in
lipid-mediated signaling is another important theme as many of
the enzymes involved in the lipid signaling pathways are Ca2⫹
regulated (Fig. 2). Moreover, the enzyme systems that require
Ca2⫹ for activation and that produce lipid mediators that
increase Ca2⫹ obtain a degree of positive feedback through this
interaction. A final important theme is the role of lipid mediators in inflammatory reactions. PGs, leukotrienes, PAF, and
lysophospholipids are all lipid mediators in various aspects of
inflammatory reactions.
The field of lipid signal transduction is complicated. The
difficulty of visualizing lipid biochemistry, the lower profile of
lipid signaling compared with protein signaling, and the many
“black holes” that remain in our understanding of lipid signaling all contribute to the complicated nature of lipid signal
transduction. Certainly, there are many details of lipid signaling that must be worked out. The relatively recent identification of messenger functions of C1P and sphingosylphosphorylcholine support the concept that other lipid mediators remain to be discovered. This review provides a framework in
which to place those new details of lipid signaling as they
emerge. Moreover, this review illustrates the magnitude and
diversity of lipid mediators in signal transduction and highlights the importance of staying current in the roles of lipid
mediators in cellular physiology.
GRANTS
This work was supported in part by National Science Foundation Grant
IBN-0315717.
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