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PHYSIOLOGY 28: 423– 431, 2013; doi:10.1152/physiol.00023.2013
Mechanism and Physiological
Significance of Growth Factor-Related
Autophagy
Terytty Yang Li, Shu-Yong Lin,
and Sheng-Cai Lin
State Key Laboratory of Cellular Stress Biology, School of Life
Sciences, Xiamen University, Xiamen, Fujian, China
[email protected]
Growth factors, typically defined as natural substances capable of stimulating
cell growth and differentiation, are vital regulators for the survival of metazoan
cells. In this review, we will focus on growth factor signaling pathways that are
closely related to autophagy induction and discuss the critical roles of this
fascinating cellular process in intracellular energy homeostasis, cell fate determination, and pathophysiological regulation.
1548-9213/13 ©2013 Int. Union Physiol. Sci./Am. Physiol. Soc.
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One of the most intriguing phenomena about metazoan cells, as opposed to unicellular eukaryotes, is
that their survival depends on not only sufficient
surrounding nutrients but also growth factors (71).
When binding to their cognate receptors on the cell
surface, growth factors facilitate cellular anabolic
metabolism by stimulating the uptake and usage of
nutrients such as glucose (119, 123), amino acids
(96), and glutamine (124) through the translocalization or upregulation of nutrient transporters onto the
cell surface. Growth factors exert their growthstimulating roles by activating various signaling
pathways, among which the phosphoinositide 3-kinase (PI3K)-AKT pathway appears to play a dominant role. Together, these effects maintain cell
energy supply and biosynthesis of various intermediates like nucleotides, amino acids, and fatty acids,
which prepare cells for the needs of rapid proliferation, including embryonic development (68), wound
healing (3, 126), and cancer progression (128). Not
surprisingly, some cells become cancerous after acquiring mutations or altered expression of growth
factor signaling-related molecules to engender a
state that mimics constant growth factor input and
thus sustains dysregulated nutrient uptake and
metabolism (63, 118).
Upon growth factor deprivation, cells begin to
use intracellular resources to meet the basic requirements of energy and metabolites, a process
known as catabolic metabolism, in that autophagy
is a critical one (56, 93, 109). Autophagy is typically
classified into three types, microautophagy, chaperone-mediated autophagy, and macroautophagy.
Microautophagy is the direct engulfment of cytosol
components by lysosome membrane (84), and
chaperone-mediated autophagy occurs when proteins are specifically recognized by chaperone heat
shock cognate 70 (hsc70) and subsequently transferred to lysosome and degraded (46). Most of our
current knowledge about growth factor-related
autophagy, however, comes from the study of
macroautophagy (56, 93, 134, 135). Defined as a
self-degradation process in that cytosolic components, including unnecessary organelles, are
engulfed inside the double-membraned vesicle
named autophagosome and subsequently degraded after the autophagosome fuses with the
lysosome, macroautophagy (hereafter referred to
as autophagy) benefits cell survival under multitudes of stress conditions, such as glucose starvation (47), amino acids depletion (88), treatment of
cytotoxic stressors (95), infection of pathogens
(60), hypoxia (36), and growth factor deprivation
(69). In the past few decades, extensive studies in
yeast and multicellular organisms alike have revealed a great number of genes related to autophagy (86, 134, 135). The multiple roles of
autophagy in cell growth (122), embryonic development (1, 101, 114, 142), postnatal survival (57),
glucose and lipid homeostasis (2, 31, 106, 141), and
cancer progression (13, 14, 127) were also demonstrated. Although the core autophagy-related genes
(the ATG genes) are highly conserved from yeast to
mammals (132), growth factor deprivation-induced autophagy seems to be specific for metazoans since unicellular organisms lack the growth
factor-dependent nutrients uptake system (71),
which hints at the possibility that mammalian cells
probably own a more sophisticated autophagy machinery network (4, 134, 135). Indeed, different
stimuli are capable of using different pathways to
elicit autophagy in mammals (12, 56, 90).
Early work by several independent groups of
researchers on the negative regulatory functions
of growth factors in autophagy opened up new
avenues to studying the growth factor-related
autophagy. For example, Kondo and colleagues
found that inhibition of platelet-derived growth
factor signaling was able to induce autophagy in
malignant glioma cells (110). Using C. elegans as a
model system, it was depicted that autophagy is
suppressed upon insulin-like growth factor activation (83). In another study, removal of single IL-3
from the culture medium was shown to be capable
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of inducing autophagy in apoptosis-lacking cells
(69). It is also noteworthy that some growth factors
such as TGF-␤ and TGF-␣ could reversely stimulate
autophagy under certain conditions (42, 49). However, these positive regulatory roles of the TGF factors
in autophagy induction are often associated with
their growth-inhibitory side rather than the growthstimulating effects referred to herein. Therefore, it is
probably safe to conclude that growth (stimulating)
factors are intrinsic autophagy suppressors (71).
Growth Factor-Regulated
Autophagy as a Gatekeeper for
Maintaining Cellular Homeostasis
FIGURE 1. Possible responses of mammalian cells to growth factor restriction
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In multicellular organisms, cellular metabolism is
under delicate regulatory control instructed by
growth factor signaling. Unlike unicellular organisms, metazoan cells compete for limiting growth
factors (94). Without stimulation of growth factors,
cells are reprogramed to downregulate the major
anabolic processes and adopt a catabolic metabolism designed to maximize the efficiency of ATP
production from limited nutrient uptake (18, 69,
71, 102, 118). Growing lines of evidence demonstrate that such loss of nutrient usage can directly
affect some crucial intracellular processes; for example, decrease in the levels of intermediate metabolites such as acetyl-CoA, a substrate for global
histone acetylation, leads to downregulated expression of anabolic enzymes (70, 123, 144).
Under the situation of growth factor restriction,
autophagy plays a major role in providing cells
with amino acids and lipids for the catabolic processes initiated to support the demand of ATP and
thus sustain cellular homeostasis. By digesting
their own macromolecules such as proteins and
organelles, cells cannot only obtain copious substrates for both biosynthesis and energy generation
but also eliminate damaged organelles or misfolded proteins and, therefore, to some extent prevent the generation of excess ROS and genome
instability (56, 85, 93). The importance of autophagy in facilitating cell survival is also underscored by the observation that deletion of certain
autophagy-related genes leads to a much rapid
death of cells under growth factor-deprivation conditions (69). Altogether, upon growth factor restriction, cells are forced to shut down almost all of the
proliferation-related pathways and stop most of
the anabolic processes, which is followed by the
cell cycle arrest and catabolic processes such as
oxidation of macromolecules and autophagy (118,
121, 122), although prolonged withdrawal of
growth factors will indeed lead to cell death (15)
(FIGURE 1).
Conversely, after replenishment of growth factors, cells shift the main challenge from survival
back to growth and proliferation, and initiate anabolic metabolism (125). The instructive growth
factor signaling therefore redirects cells to increase
the uptake of glucose, glutamine, and the other
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nutrients to directly support the anabolic requirement for cell proliferation and suppress autophagy
in the meantime (69).
Relationship Between Autophagy
and Apoptosis on Growth Factor
Restriction
The Signaling Network of Growth
Factor Restriction-Induced
Autophagy
Researchers have revealed elaborate signaling networks that regulate growth factor-related autophagy (FIGURE 2). The protein kinase AKT is a
central node linking growth factors to induction of
autophagy. Several pathways act upstream of AKT
to mediate growth factor signaling through distinct
routes (6). Lack of growth factor signaling often
leads to reduced AKT activity, which by default
renders AKT target substrates de-inhibited (32, 75).
Over 100 nonredundant AKT substrates, including
TSC2 (26, 27, 111), the forkhead box (FOX) O transcription factors 1/3/4 (91, 113), GSK3␣/␤ (16), and
Beclin 1, have been reported to execute diverse
biological functions (75). Importantly, these factors
are the major mediators for AKT to regulate growth
factor-related autophagy.
Upstream Signaling to AKT
Cells sense the abundance of extracellular growth
factors through a series of ligand-specific receptor
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Over the recent years, with the help of genetic tools
to disable the autophagic machinery, it is becoming more evident that, rather than a mechanism to
execute cell death, autophagy represents an antiapoptosis process and promotes cell survival under
various stimuli (54, 55, 138, 104). Especially, with
the loss of growth factor signals, the uptake of
nutrients are limited (96, 119, 123, 124) and autophagy is subsequently strongly activated (64, 69,
145). By breaking down cellular components and
recycling metabolic substrates, autophagy at such
conditions becomes the major force to maintain
regular energy homeostasis inside the cell (71, 93).
However, as more and more cellular contents are
recycled through autophagy, there is an expected
time point that cellular components are depleted.
Apoptosis or other cell death procedures, therefore,
gradually become the major theme as the restriction
of growth factor continues (73) (FIGURE 1). It is also
noteworthy that autophagy and apoptosis probably
often occur at the same time as they compete to
determine cell fate, the concept of which is further
strengthened by the fact that some molecules are
even shared by these two different processes (73, 89).
tyrosine kinases (RTKs) (62). There are ⬃20 subfamilies of RTKs in humans, all of which share a
common structure consisting of an extracellular
ligand-binding region, a single-pass transmembrane domain, and an intracellular tyrosine kinase
domain. In most cases, binding of a growth factor
to the ligand-binding domain of its cognate receptor results in the activation of this receptor kinase
and initiation of intracellular signaling cascades,
which manifests various cellular effects (62). Insulin and insulin-like growth factor I (IGFI), for example, activate their cognate receptors that, in
turn, phosphorylate adaptor proteins such as insulin receptor substrate (IRS) and Src homologous
and collagen (SHC) proteins, and the activated IRS
or SHC consequently leads to activation of the
PI3K-AKT pathway and MAPK cascade (6, 8). Similarly, other growth factors such as platelet-derived
growth factor (PDGF), epidermal growth factor
(EGF), and basic fibroblast growth factor (bFGF)
activate their respective receptors through phosphorylation of their cytoplasmic tails, which recruit specific effector molecules such as SHP-2,
Gab1, and Grb2 and further activate the PI3K-AKT
signaling (8, 130, 136).
Downstream Signaling of AKT
mTOR
mTOR is an evolutionarily conserved serine/threonine protein kinase that controls cell metabolism
and growth (20, 41, 59). Regulated by a variety of
upstream signals, mTOR is strongly repressed by
tuberous sclerosis 2 (TSC2; also known as tuberin)
and proline-rich AKT substrate 40 kDa (PRAS40)
(27, 37, 99, 111, 117). Upon growth factor restriction, AKT, along with other growth factor responding kinases such as MAPK and p90RSK1, no longer
phosphorylates and inactivates TSC2 (26, 27, 76,
92) and PRAS40 (53), which hence leads to the
inhibition of mTOR. Such suppressed mTOR then
activates autophagy due to its impaired ability to
phosphorylate and inhibit the ULK1/ATG13/FIP200
(unc-51-like kinase 1/mammalian autophagy-related
gene 13/focal adhesion kinase family-interacting
protein of 200 kDa) complex that belongs to the
autophagy initiation core machinery (25, 35, 45). In
addition, mTOR is also implicated to suppress autophagy during the step of lysosome activation (146).
GSK3
GSK3 is one of the most classic AKT substrates (16).
The activity of GSK3 is inversely regulated by phosphorylation by AKT; in other words, in the absence
of AKT activity, GSK3 becomes active after deinhibition. In addition to common growth factors, developmental morphogens that promote cell
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autophagy initiation (64). Genetic hints for the
emerging roles of TIP60 (Esa1 in yeast) as an essential
autophagy regulator was also obtained in yeast and
fruit flies (58, 137). In support of a positive role of
GSK3 in autophagy, it was demonstrated that interleukin 17A inhibits autophagy through inactivating
GSK3␤ (66), and activation of GSK3 by ROS was
shown to promote autophagy (67).
FOXO
Apart from regulation of signaling molecules, growth
factor-stimulated AKT can directly phosphorylate the
forkhead box (FOX) O transcription factors, which
are consequently excluded from the nucleus and inactivated (7, 50). In the absence of growth factors,
decreased PI3K-AKT signaling leads to increased
transcriptional activity of FOXO3, inducing the expression of several core autophagy genes, such as
LC3B and Gabarapl1 (19, 74, 103, 143). Interestingly,
it was shown that the AKT-FOXO3 axis is involved in
autophagy induction in skeletal muscle (74), and instead inhibition of mTOR by rapamycin is not able to
initiate this process. These findings suggest that selective usages of the distinct signaling cascades may
exist in different cells or tissues. In addition to direct
transactivation of the autophagy core molecules,
FOXO could upregulate glutamine synthetase for glutamine production, which results in mTOR inhibition and ultimately autophagy induction (116). Of
note, a transactivation-independent mechanism for
FOXO has been suggested by a report showing that,
under serum starvation conditions, cytosolic FOXO1
became heavily acetylated after dissociating from
histone deacetylase SIRT2 and in turn bound to
ATG7 to promote autophagy (145), although it was
disputed that, upon activation, FOXO1 is mostly
translocated into the nucleus (82).
Beclin 1
Moreover, the core autophagy machinery has also
been shown to be directly targeted by AKT. Wang
et al. (120) demonstrated that AKT directly phosphorylates Beclin 1, a Bcl-2 interacting coiled-coil
protein, and the mammalian othologue of yeast
Atg6, leading to dissociation of the autophagy-activating Beclin 1-VPS34 complex and inhibition of
autophagy.
AMPK
FIGURE 2. Signaling network of growth factor restriction-induced
autophagy
The protein kinase AKT is a central node linking growth factor signaling to downstream pathways that related to autophagy induction. In the presence of growth factors, AKT phosphorylates a wide array of substrates, including TSC2, PRAS40, GSK3,
FOXO, and Beclin 1, leading to their inactivation. Conversely, growth factor restriction
could result in de-inhibition of these substrates and subsequent initiation of autophagy
through different pathways.
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AMPK is the major sensor of cellular energy status
and is implicated as critical in glucose starvationinduced autophagy (21, 30, 47). In response to acute
energy depletion caused by hypoxia, exercise, or
glucose deprivation, AMPK is activated by phosphorylation at Thr172, which is mainly catalyzed by the
liver kinase B1 (LKB1) (30). Not surprisingly, upon
glucose deprivation, AMPK activates ULK1 through
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growth, such as Wnt and hedgehog ligands, also
participate in the regulation of autophagy by modulating GSK3 activity (43, 105, 131). This feature
makes GSK3 an inherent sensor for the abundance
of a large variety of growth factors. GSK3 can phosphorylate TSC2, leading to mTOR inactivation (38).
Direct inhibition of GSK3 by specific chemical inhibitors attenuates autophagy, which was proposed to be due to mTOR being activated (100).
Another pivotal direct target of GSK3 for the regulation of growth factor-related autophagy is the
acetyltransferase TIP60, also known as K (lysine)acetyltransferase 5 or KAT5. Upon growth factor deprivation, de-inhibited GSK3 phosphorylates and
increases the enzymatic activity of TIP60, which in
turn acetylates and activates ULK1, leading to
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Pathophysiological Functions of
Growth Factor-Related Autophagy
Autophagy is now widely implicated in pathophysiological processes such as cancer, neurodegenerative
disorders, aging, and cardiovascular and pulmonary
diseases (14). Below, we will focus on the possible
roles of growth factor-related autophagy as a pathophysiogical mediator and potential target for therapeutic intervention (FIGURE 3).
Increasing evidence supports the claim that autophagy is a double-edged sword in tumorigenesis
(14, 48, 65, 127). On one hand, autophagy has been
depicted to be capable of guarding against tumorigenesis by processes such as limiting inflammation, eliminating toxic unfolded proteins, and
removing damaged mitochondria that may produce cytotoxic reactive oxygen species (28, 79, 80,
127). Loss of autophagy by genetically targeting
core autophagy machinery is also reported to result in tumor development (77, 108, 140). Recently,
direct evidence linking the loss of growth factorrelated autophagy to cancer development has been
shown (51, 120). Furthermore, since cancer cells
often gain mutations of the critical regulators in
growth factor-sensing machineries, such as PIK3CA,
AKT, PTEN, TSC2, and Ras, they display constitutive
cell proliferation independent of growth factors. Importantly, the mutations may dampen autophagy
activity. It remains to be seen whether lack of autophagy in the settings of oncogenic mutations
would facilitate cancer development or progression
(5, 17, 33, 44, 107, 139, 147).
On the other hand, autophagy may also endow the cancer cells with the ability to survive in
nutrient-poor conditions through multiple processes (9, 10, 23, 29). Suppression of autophagy
hence conversely renders cancer cell more apt to
death. For instance, Yang et al. reported that inhibition of autophagy leads to a robust tumor regression and prolonged survival in pancreatic cancer
xenografts and genetic mouse models (133). Moreover, in Tsc2-null cells, which exhibit high mTOR
activity and likely own low autophagy activity, are
hypersentitive to energy deprivation-induced
apoptosis (39). Such phenomena have been especially instructive for cancer therapy since tumor
cells exposed to traditional radio- or chemotherapy
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phosphorylation and induces autophagy (21, 47), but
what about the growth factor restriction conditions?
AKT signaling, in the stimulation of insulin, negatively regulates the Thr172 phosphorylation of cardiac AMPK (34, 52). In addition, under Wnt
stimulation, AMPK phosphorylates TSC2, suppressor
of mTOR (38). However, as our previous work demonstrated, even prolonged growth factor deprivation,
different from glucose starvation, did not seem to
activate AMPK-ULK1 pathway in MEFs (64). The effects of growth factors on AMPK activation and its
ability in autophagy induction upon growth factor
deprivation therefore probably require more indepth investigation under different tissues and
stimulation situations.
FIGURE 3. Advantages and disadvantages of growth factor-related autophagy in physiology
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Conclusions and Perspectives
The past few decades have witnessed tremendous
advances in our knowledge of autophagy, both in
its molecular mechanisms and its pathophysiological functions. Activated by various stimuli, autophagy has been considered as one of the most
important links between availability of extracellular nutrients and intracellular metabolism. In
mammalian cells, such a link is heavily dependent
on the availability of growth factors. Despite the
delineation of the AKT-mTOR-ULK1, AKT-GSK3ULK1, and AKT-FOXO signaling routes, much has
to be learned about the molecular mechanisms
and functions of autophagy induced by limited
growth factors. One of the major challenges is to
determine how these different signaling modes are
preferentially utilized in response to limitation of
growth factors or extracellular nutrients, although
AKT activity may play a general upstream role in
controlling the activity of GSK3, mTOR, and FOXO.
For instance, Goldberg and colleagues demonstrated that AKT-FOXO route rather than AKTmTOR route is adopted in muscle autophagy (143).
In our study, the GSK3-TIP60-ULK1 route seems to
have no contribution to the glucose deprivationinduced autophagy (64).
Equally puzzling is how the distinct pathways
cross talk to each other. Preliminary work has implicated interrelationships between components of
these distinct pathways. Inoki et al. demonstrated
that GSK3 and AMPK cooperatively phosphorylate
TSC2 and inhibit mTOR (38). Activation of FOXO
could also inhibit mTOR by elevating glutamine
production (116). In addition, upon stimulation by
DNA damage, GSK3-TIP60 axis acetylates and activates p53 (11), which shares a wide array of
transcription targets with FOXO. Whether p53 activation by GSK3-TIP60 is also utilized in growth
factor-related autophagy remains to be tested.
What other mechanisms may be associated with
the individual components that participate in these
pathways is another interesting question. TIP60, for
example, is the key component in a transcription
co-regulator complex, acting for a range of transcription factors. Does it have any role resembling
the one FOXO played in changing the transcriptional programs in cells induced to undergo autophagy? Furthermore, although cells do undergo
death after prolonged growth factor deprivation
(15), little is known about how the stressed cells
exactly die. The molecular switch controlling the
fate of the cells to live or to die deserves to be
established. There is no doubt that understanding
of these open questions will be enormously beneficial in providing effective therapeutic approaches for detection, treatment, and control of
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often activate autophagy to promote survival and
become resistant to these treatments. Blockage of
autophagy is therefore considered as a promising
complementary way to promote cancer cell death
and to improve patient survival during clinical
cancer therapy (112).
Many studies have implicated autophagy in the
aging process. Genetic inhibition of autophagy induces aging-like degenerative changes in mammalian tissues, and that pathological aging, and
normal aging alike, is often associated with a reduced autophagic potential (78, 97). The longevitypromoting effect of autophagy could probably be
reached through several ways. First of all, the accumulation of misfolded or aggregated proteins,
like beta-amyloid and damaged organelles, which
strongly facilitate the aging process, can be effectively prevented through autophagy (19, 26, 40,
129). Second, autophagy could also reduce inflammatory cytokine secretion and spontaneous tumor
incidence (72, 98). Furthermore, consistent with a
correlation between autophagy and aging, aging is
demonstrated to be negatively associated with serum concentrations of several growth factors and
anabolic hormones. For example, the circulating
levels of GH, IGF-I, sex hormones, and DHEAs
progressively decline between 20 and 80 years of
age in humans (61). Finally, artificially stimulating
growth factor-related autophagy pathways has recently been shown to promote longevity in different model systems. For example, the FOXO family,
which is a direct executor in growth factor signaling and a classic autophagy stimulator, has been
widely recognized as an aging promoter in both
yeast and other organisms (22, 115). In another
study using cardiomyocytes as a model system,
specific expression of dominant-negative PI3K,
which also activates autophagy, leads to reduced
lipofuscin levels in the heart and increased longevity (24, 40). Thus manipulation of growth factorrelated autophagy could be a potential way to
delay aging.
Suppression of autophagy has also been shown
to be a potential therapy for some diseases that are
caused, at least in part, as a result of dysregulated
autophagy. Recognized as one of the leading causes
of infant mortality, necrotizing enterocolitis (NEC) is
a common but devastating gastrointestinal disease
primarily seen in premature infants (87). The pathogenesis of this disorder is not fully understood, yet it
probably involves over-induction of autophagy. Maynard et al. demonstrated that admission of epidermal
growth factor (EGF) could strongly block the autophagy activity in the intestinal epithelium from
patients with NEC and reduce the death rate of epithelial cells, leading to protection of the intestinal
epithelium against mucosal injury (81).
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diseases caused by altered growth factor-related
autophagy. 䡲
Our work is supported by grants from the National Natural Science Foundation of China (no. 31130016 and no.
31221065), the “111” Project of Ministry of Education of
China (no. B06016), and the Fundamental Research Funds
for the Xiamen Universities (grant no. 201112G021). S.-C.
Lin is a Cheung Kong Scholar.
No conflicts of interest, financial or otherwise, are declared by the author(s).
Author contributions: T.Y.L. and S.-Y.L. prepared figures;
T.Y.L. and S.-Y.L. drafted manuscript; T.Y.L., S.-Y.L., and S.C.L. edited and revised manuscript; T.Y.L., S.-Y.L., and S.-C.L.
approved final version of manuscript.
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