ARTICLE
Auteur(s) : Mario
Pende
Avenir Team, Inserm U810, Faculté de médecine Necker-Enfants
malades, Université Paris V, 156 rue de Vaugirard, 75730 Paris
Cedex 15
A pathway controlling body size
Body size depends on cell number and cell size. The control of cell
number relies on the cell cycle and apoptosis machineries, while
the process regulating cell size is defined as cell growth. Over
the last decade genetic studies in Drosophila melanogaster have
identified gene products that are activated by insulin/IGF
receptors and affect organ mass. Among them, the insulin receptor
substrate (IRS) [1], phosphatidyl inositide 3-OH kinase (PI3K) [2],
the small GTPase Rheb [3-5], and the serine/threonine kinases Akt
[6], target of rapamycin (TOR) [7, 8], and S6 kinase (S6K) [9].
The function of this pathway is conserved in mammals as
indicated by the small body weight of mice carrying inactivating
mutations in the orthologous genes [10]. During metazoan evolution,
gene duplication has increased the number of Akt (Akt1 to 3 or PKBα
to γ, in mice and humans) and S6K family members (S6K1-2 or S6Kα
and β, in mice and humans), while the TOR gene is unique in mammals
(mTOR). The central role of mTOR in growth, proliferation and
development is demonstrated by the dramatic phenotype of the
mTOR-/- embryos that do not survive after the
implantation stage [11, 12]. With regards to the Akt and S6K family
members, despite the sequence similarities and some functional
redundancy, the growth defect is more pronounced in the Akt1- and
S6K1-deficient mice [13-16]. Akt2 deletion has only a minor effect
on weight [17], Akt3 deletion selectively affects brain size [18,
19] and S6K2 inactivation has no effect on total body size [20],
suggesting a certain degree of specificity in the growth-activating
functions of these kinases. However it is clear that the Akt and
S6K family members also serve redundant functions, as outlined by
the deterioration of the phenotype when two mutations are combined.
Akt1;Akt2-/- and Akt1;Akt3-/- embryos die in
utero [21, 22], while the S6K1;S6K2-/- mice die at the
perinatal stage [20]. In conclusion, the severity of the phenotype
due to inactivating mutations decreases from mTOR- to Akt- to
S6K-null mice, consistent with what is known about the interactions
and the pleiotropy of these genes (see below).
Growth signal transduction
mTOR, Akt and S6K are serine/threonine kinases that transduce the
anabolic signals from the plasma membrane to the intracellular
effectors. mTOR protein resides in proximity to the plasma membrane
in two distinct large protein complexes, integrating the growth
stimuli from the environment [23]. The signals activating mTOR
complexes can be divided in two classes: the growth factor peptides
such as insulin and IGFs, and the nutrients, such as amino acids
and glucose (( figure
1 )). The growth factor effect on mTOR requires class Ia
PI3K and Rheb activity [24], while nutrients require class III PI3K
activity [25, 26]. In addition mTOR senses the general availability
of the substrates for respiration. When the ATP and oxygen levels
are optimal for growth, mTOR is relieved by the AMPK and Redd1
inhibitory input [27-29]. This complex regulation makes mTOR a key
element coupling the growth factor signals with the metabolic
activity of the cell.
Over the last few years, the Sabatini and Hall laboratories have
shed light on the role of the two mTOR complexes in mammalian
cells. The one comprising mTOR, raptor and GβL (also named mLST8)
proteins requires the combined presence of nutrients and growth
factors for activity and is sensitive to the inhibitory action of
rapamycin [30, 31]. The second comprises rictor (also named mAVO3)
as mTOR- and GβL- partner instead of raptor, and is activated by
growth factors in a rapamycin- and possibly nutrient- insensitive
manner [32-34]. Depending on the partners, mTOR phosphorylates
distinct substrates. mTOR/rictor phosphorylates Akt on Ser473, and
possibly other kinases of the AGC family on the homologous site in
the hydrophobic motif needed for activation [34]. The presence of
raptor in the mTOR complex redirects mTOR towards S6K1 and 2, that
are phosphorylated in the hydrophobic motif on Thr389 and Thr388
respectively [35]. This proposed mechanism would explain why S6K
activity is nutrient- and rapamycin-sensitive while Akt activity is
not.
An intense cross talk exists between mTOR, Akt and S6K, possibly
due to the dynamic association of the mTOR complexes. Constitutive
activation of Akt by membrane targeting or by PTEN deletion,
upregulates the nutrient-S6K branch of the mTOR pathway through the
phosphorylation of TSC2, that controls Rheb activity [36, 37].
Since Akt and S6K do not interact epistatically in Drosophila flies
[38], it has been debated whether this regulation is
physiologically relevant or is a response to a pathological
stimulation of the Akt pathway. However recent loss-of-function
studies in mice confirm the positive role of Akt on S6K activation
[18, 21]. In contrast, S6K activity provides a negative feedback on
the growth factor-Akt branch of the mTOR pathway. This inhibitory
loop has been first unveiled in rapamycin treated cells [39], and
then observed in a variety of conditions and cell types [38,
40-42]. The proposed model to explain these findings is the
S6K-mediated IRS-1 phosphorylation on serine residues that leads to
IRS-1 degradation or inactivation. Alternatively S6K may interfere
with mTOR complex composition. Consistent with this possibility,
S6K directly phosphorylates mTOR on Ser2448 [43]. Although this
event does not modify the catalytic activity of mTOR, it might
favour the binding of specific partners and mediate the cross talk
between the mTOR/Akt/S6K kinases. In conclusion we can speculate
that growth factors via mTOR-rictor-Akt up-regulates nutrient
signalling through the mTOR-raptor-S6K pathway. In turn this
pathway provides a “satiety signal” that down regulates further Akt
activity. However two key experiments are needed before drawing
this conclusion. First, it is not clear yet whether the rictor
knockout decreases the mTOR/raptor activity. Second, the direct
target of S6K involved in the retro control of the growth factor
pathway has to be identified.
Skeletal muscle growth
How do the mTOR, Akt and S6K kinases act on cell growth? What are
their downstream effectors? How are growth and proliferation
coordinated? Here we will review how these questions have been
partially addressed in mammalian skeletal muscles. The mass of this
tissue increases in three ways: by hyperplasia resulting in an
increase in fiber number, by hypertrophy due to myoblast fusion,
and by hypertrophy through an increase in cytoplasmic volume. The
number of fibers is usually set during development while their size
continuously adapts during the entire lifetime depending on
activity, nutrition, diseases and aging. Importantly,
proliferation, growth and differentiation of muscle cells can be
recapitulated in vitro using myoblast cultures and proper mitogens
and growth factors [44]. IGF signalling is required at multiple
steps of muscle cell function [45-50], and Akt activation mimics
the majority of IGF effects. Depending on the presence of mitogens
and the developmental stage, membrane targeted Akt may accelerate
myoblast cell cycle progression [51], induce the myogenic process
by promoting cell differentiation [52-54] and finally stimulate
muscle hypertrophy in cultures [51, 55] as well as in mice [56-58].
Relevant to muscle wasting diseases, this constitutively active
form of Akt also protects against muscle atrophy due to
denervation, starvation or glucocorticoid treatment [56, 57, 59,
60]. Consistent with these findings, severe muscle atrophy has been
observed in embryos lacking Akt1 and Akt2, despite the residual
Akt3 activity [21]. Remarkably, the overall phenotype of these
mutant embryos resemble the one caused by IGF1 receptor
inactivation, confirming the key role of Akt in IGF-regulated
mammalian development.
As seen in the previous section, Akt may function in muscle
cells by facilitating the nutrient signalling through mTOR/raptor
and/or by directly regulating multiple targets downstream of
mTOR/rictor (( figure
1 )). While waiting for the genetic alteration of specific
mTOR complex components, the use of the mTOR/raptor inhibitor
rapamycin and the S6K deletion has allowed us to dissect the
contribution of these elements. Rapamycin partially inhibits the
effect of active Akt on myoblast proliferation while S6K deletion
does not affect muscle cell cycle [51], indicating that mTOR/raptor
has additional as yet unknown targets for cell cycle regulation. In
addition, rapamycin blocks the Akt-induced hypertrophy of muscle
fibers [51, 55-57] (( figure 2 )). This is
physiologically relevant because mTOR/raptor inhibition also
impairs growth during skeletal muscle load or recovery from atrophy
[56]. In contrast to what is observed for cell cycle progression,
the control of muscle cell size requires S6K activity. The single
deletion of S6K1 is sufficient to mimic the effect of rapamycin on
myoblast and myotube cell size, considerably blunting the
stimulatory action of IGF1 and membrane targeted Akt on muscle
growth [51]. S6K1-/- muscle fibers are thinner than wild
type due to a reduction of cytosolic volume with no defect in cell
fusion. Moreover, they are resistant to nutrient deprivation,
indicating a fundamental role of this kinase during muscle
remodelling after starvation/refeeding. Strikingly, these data
demonstrate that muscle cell number and size are controlled by
distinct branches downstream of the mTOR/raptor, and identify S6K1
as an essential effector for muscle cell growth.
S6K1 phosphorylates the ribosomal protein S6 (rpS6) on five
serine residues in the C-terminal tail [61]. In addition other
proteins belonging to the translational machinery are S6K1
substrates, such as the initiation factor eIF4B [62], the
elongation factor 2 kinase (eEF2K) [63], and the RNA binding
protein SKAR [64]. S6K1 is also found in a translation
pre-initiation complex associated with eIF3 [65]. This evidence has
led to the hypothesis that S6K1 may regulate cell growth by a
direct stimulation of protein synthesis. Potential candidates for
regulation are mRNA classes that require mTOR/raptor activity to be
translated, such as the mRNAs starting with a 5’ terminal
oligopyrimidine tract (5’TOP) that encode for proteins involved in
ribosome biogenesis [66]. However, data from the S6K deficient mice
do not support this conclusion yet. S6K2 can compensate for the
loss of S6K1 with regards to S6 phosphorylation but does not
promote muscle growth, indicating that S6 phosphorylation does not
correlate with cell growth [51]. Moreover since no defect of 5’TOP
translation has been reported in S6K null fibroblasts or embryonic
stem cells [20], the molecular mechanisms of S6K1 dependent muscle
growth has to be uncovered yet.
While mTOR/raptor/S6K1 is required for muscle hypertrophy, the
inhibition of this pathway by rapamycin does not induce a
significant muscle atrophy in adult animals [56, 57]. All forms of
muscle atrophy are characterised by the expression of two genes
encoding E3 ubiquitin ligases, MuRF-1 and atrogin-1 (also known as
MAFbx), an event that is sufficient to induce protein degradation
and muscle wasting [67-69]. MuRF1 and atrogin-1 promoters are
controlled by the FOXO family of transcription factors [59, 60].
Interestingly, FOXOs are Akt substrates that are excluded from the
nucleus upon phosphorylation. Thus the mTOR/Akt pathway has a dual
growth-promoting function in skeletal muscle. First mTOR/rictor/Akt
suppresses a default catabolic process through the direct
phosphorylation of FOXO. When a threshold of Akt activity has been
reached to allow sustained activation of the nutrient dependent
branch of the pathway, the mTOR/raptor/S6K1 module signals to
hypertrophy.
Despite this progress in our understanding of muscle cell
growth, many issues remain open. How does S6K1 promote muscle
hypertrophy? How do nutrients drive cell cycle progression? What
are the additional targets of mTOR/rictor? Are there any other mTOR
complexes? Do mutations in the mTOR complex components cause
myopathies? These are fundamental questions of cell biology that
will certainly generate knowledge and shed light on the
pathogenesis of muscle disease.
Acknowledgements
We are grateful to M. Freemark and members of Inserm U810 for
reading the manuscript and helpful discussions.
References
1 Bohni R, Riesgo-Escovar J, Oldham S,
Brogiolo W, Stocker H, Andruss BF, et al.
Autonomous control of cell and organ size by CHICO, a Drosophila
homolog of vertebrate IRS1-4. Cell 1999; 97: 865-75.
2 Leevers SJ, Weinkove D, MacDougall LK,
Hafen E, Waterfield MD. The Drosophila phosphoinositide
3-kinase Dp110 promotes cell growth. EMBO J 1996; 15: 6584-94.
3 Stocker H, Radimerski T, Schindelholz B,
Wittwer F, Belawat P, Daram P, et al. Rheb is
an essential regulator of S6K in controlling cell growth in
Drosophila. Nat Cell Biol 2003; 5: 559-65.
4 Saucedo LJ, Gao X, Chiarelli DA, Li L,
Pan D, Edgar BA. Rheb promotes cell growth as a component
of the insulin/TOR signalling network. Nat Cell Biol 2003; 5:
566-71.
5 Zhang Y, Gao X, Saucedo LJ, Ru B,
Edgar BA, Pan D. Rheb is a direct target of the tuberous
sclerosis tumour suppressor proteins. Nat Cell Biol 2003; 5:
578-81.
6 Verdu J, Buratovich MA, Wilder EL,
Birnbaum MJ. Cell-autonomous regulation of cell and organ
growth in Drosophila by Akt/PKB. Nat Cell Biol 1999; 1: 500-6.
7 Oldham S, Montagne J, Radimerski T,
Thomas G, Hafen E. Genetic and biochemical
characterization of dTOR, the Drosophila homolog of the target of
rapamycin. Genes Dev 2000; 14: 2689-94.
8 Zhang H, Stallock JP, Ng JC, Reinhard C,
Neufeld TP. Regulation of cellular growth by the Drosophila
target of rapamycin dTOR. Genes Dev 2000; 14: 2712-24.
9 Montagne J, Stewart MJ, Stocker H,
Hafen E, Kozma SC, Thomas G. Drosophila S6 kinase: a
regulator of cell size. Science 1999; 285: 2126-9.
10 Lupu F, Terwilliger JD, Lee K, Segre GV,
Efstratiadis A. Roles of growth hormone and insulin-like
growth factor 1 in mouse postnatal growth. Dev Biol 2001; 229:
141-62.
11 Murakami M, Ichisaka T, Maeda M,
Oshiro N, Hara K, Edenhofer F, et al. mTOR is
essential for growth and proliferation in early mouse embryos and
embryonic stem cells. Mol Cell Biol 2004; 24: 6710-8.
12 Gangloff YG, Mueller M, Dann SG,
Svoboda P, Sticker M, Spetz JF, et al.
Disruption of the mouse mTOR gene leads to early postimplantation
lethality and prohibits embryonic stem cell development. Mol Cell
Biol 2004; 24: 9508-16.
13 Shima H, Pende M, Chen Y, Fumagalli S,
Thomas G, Kozma SC. Disruption of the p70(s6k)/p85(s6k)
gene reveals a small mouse phenotype and a new functional S6
kinase. EMBO J 1998; 17: 6649-59.
14 Cho H, Thorvaldsen JL, Chu Q, Feng F,
Birnbaum MJ. Akt1/PKBalpha is required for normal growth but
dispensable for maintenance of glucose homeostasis in mice. J Biol
Chem 2001; 276: 38349-52.
15 Chen WS, Xu PZ, Gottlob K, Chen ML,
Sokol K, Shiyanova T, et al. Growth retardation and
increased apoptosis in mice with homozygous disruption of the Akt1
gene. Genes Dev 2001; 15: 2203-8.
16 Yang ZZ, Tschopp O, Hemmings-Mieszczak M,
Feng J, Brodbeck D, Perentes E, et al. Protein
kinase B alpha/Akt1 regulates placental development and fetal
growth. J Biol Chem 2003; 278: 32124-31.
17 Garofalo RS, Orena SJ, Rafidi K,
Torchia AJ, Stock JL, Hildebrandt AL, et al.
Severe diabetes, age-dependent loss of adipose tissue, and mild
growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest
2003; 112: 197-208.
18 Easton RM, Cho H, Roovers K, Shineman DW,
Mizrahi M, Forman MS, et al. Role for Akt3/protein
kinase Bgamma in attainment of normal brain size. Mol Cell Biol
2005; 25: 1869-78.
19 Tschopp O, Yang ZZ, Brodbeck D,
Dummler BA, Hemmings-Mieszczak M, Watanabe T,
et al. Essential role of protein kinase B gamma (PKB
gamma/Akt3) in postnatal brain development but not in glucose
homeostasis. Development 2005; 132: 2943-54.
20 Pende M, Um SH, Mieulet V, Sticker M,
Goss VL, Mestan J, et al. S6K1(-/-)/S6K2(-/-) mice
exhibit perinatal lethality and rapamycin-sensitive 5’-terminal
oligopyrimidine mRNA Translation and reveal a mitogen-activated
protein kinase-dependent S6 kinase pathway. Mol Cell Biol 2004; 24:
3112-24.
21 Peng XD, Xu PZ, Chen ML,
Hahn-Windgassen A, Skeen J, Jacobs J, et al.
Dwarfism, impaired skin development, skeletal muscle atrophy,
delayed bone development, and impeded adipogenesis in mice lacking
Akt1 and Akt2. Genes Dev 2003; 17: 1352-65.
22 Yang ZZ, Tschopp O, Di Poi N, Bruder E,
Baudry A, Dummler B, et al. Dosage-dependent effects
of Akt1/protein kinase Balpha (PKBalpha) and Akt3/PKBgamma on
thymus, skin, and cardiovascular and nervous system development in
mice. Mol Cell Biol 2005; 25: 10407-18.
23 Sarbassov DD, Ali SM, Sabatini DM. Growing
roles for the mTOR pathway. Curr Opin Cell Biol 2005; 17:
596-603.
24 Garami A, Zwartkruis FJ, Nobukuni T,
Joaquin M, Roccio M, Stocker H, et al. Insulin
activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is
inhibited by TSC1 and 2. Mol Cell 2003; 11: 1457-66.
25 Nobukuni T, Joaquin M, Roccio M, Dann SG,
Kim SY, Gulati P, et al. Amino acids mediate
mTOR/raptor signaling through activation of class 3
phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci USA 2005; 102:
14238-43.
26 Byfield MP, Murray JT, Backer JM. hVps34 is a
nutrient-regulated lipid kinase required for activation of p70 S6
kinase. J Biol Chem 2005; 280: 33076-82.
27 Inoki K, Zhu T, Guan KL. TSC2 mediates
cellular energy response to control cell growth and survival. Cell
2003; 115: 577-90.
28 Brugarolas J, Lei K, Hurley RL,
Manning BD, Reiling JH, Hafen E, et al.
Regulation of mTOR function in response to hypoxia by REDD1 and the
TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18:
2893-904.
29 Sofer A, Lei K, Johannessen CM,
Ellisen LW. Regulation of mTOR and cell growth in response to
energy stress by REDD1. Mol Cell Biol 2005; 25: 5834-45.
30 Kim DH, Sarbassov DD, Ali SM, King JE,
Latek RR, Erdjument-Bromage H, et al. mTOR interacts
with raptor to form a nutrient-sensitive complex that signals to
the cell growth machinery. Cell 2002; 110: 163-75.
31 Kim DH, Sarbassov DD, Ali SM, Latek RR,
Guntur KV, Erdjument-Bromage H, et al. GbetaL, a
positive regulator of the rapamycin-sensitive pathway required for
the nutrient-sensitive interaction between raptor and mTOR. Mol
Cell 2003; 11: 895-904.
32 Jacinto E, Loewith R, Schmidt A, Lin S,
Ruegg MA, Hall A, et al. Mammalian TOR complex 2
controls the actin cytoskeleton and is rapamycin insensitive. Nat
Cell Biol 2004; 6: 1122-8.
33 Sarbassov DD, Ali SM, Kim DH, Guertin DA,
Latek RR, Erdjument-Bromage H, et al. Rictor, a
novel binding partner of mTOR, defines a rapamycin-insensitive and
raptor-independent pathway that regulates the cytoskeleton. Curr
Biol 2004; 14: 1296-302.
34 Sarbassov DD, Guertin DA, Ali SM,
Sabatini DM. Phosphorylation and regulation of Akt/PKB by the
rictor-mTOR complex. Science 2005; 307: 1098-101.
35 Ali SM, Sabatini DM. Structure of S6 kinase 1
determines whether raptor-mTOR or Rictor-mTOR phosphorylates its
hydrophobic motif site. J Biol Chem 2005; 280: 19445-8.
36 Manning BD, Tee AR, Logsdon MN, Blenis J,
Cantley LC. Identification of the tuberous sclerosis complex-2
tumor suppressor gene product tuberin as a target of the
phosphoinositide 3-kinase/akt pathway. Mol Cell 2002; 10:
151-62.
37 Inoki K, Li Y, Zhu T, Wu J, Guan KL.
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR
signalling. Nat Cell Biol 2002; 4: 648-57.
38 Radimerski T, Montagne J, Rintelen F,
Stocker H, van der KJ, Downes CP, et al.
dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but
requires dPDK1. Nat Cell Biol 2002; 4: 251-5.
39 Haruta T, Uno T, Kawahara J, Takano A,
Egawa K, Sharma PM, et al. A rapamycin-sensitive
pathway down-regulates insulin signaling via phosphorylation and
proteasomal degradation of insulin receptor substrate-1. Mol
Endocrinol 2000; 14: 783-94.
40 Harrington LS, Findlay GM, Gray A,
Tolkacheva T, Wigfield S, Rebholz H, et al. The
TSC1-2 tumor suppressor controls insulin-PI3K signaling via
regulation of IRS proteins. J Cell Biol 2004; 166: 213-23.
41 Um SH, Frigerio F, Watanabe M, Picard F,
Joaquin M, Sticker M, et al. Absence of S6K1
protects against age- and diet-induced obesity while enhancing
insulin sensitivity. Nature 2004; 431: 200-5.
42 Manning BD, Logsdon MN, Lipovsky AI,
Abbott D, Kwiatkowski DJ, Cantley LC. Feedback
inhibition of Akt signaling limits the growth of tumors lacking
Tsc2. Genes Dev 2005; 19: 1773-8.
43 Holz MK, Blenis J. Identification of S6 kinase 1 as
a novel mammalian target of rapamycin (mTOR)-phosphorylating
kinase. J Biol Chem 2005; 280: 26089-93.
44 Pinset C, Montarras D. Cell system for ex-vivo
studies of myogenesis: a protocol for the isolation of stable
muscle cell populations from newborn to adult mice. In:
Celis J, ed. Cell Biology, a laboratory handbook. New York:
Academic press, 1998.
45 Florini JR, Magri KA, Ewton DZ, James PL,
Grindstaff K, Rotwein PS. Spontaneous" differentiation of
skeletal myoblasts is dependent upon autocrine secretion of
insulin-like growth factor-II. J Biol Chem 1991; 266: 15917-23.
46 Coleman ME, DeMayo F, Yin KC, Lee HM,
Geske R, Montgomery C, et al. Myogenic vector
expression of insulin-like growth factor I stimulates muscle cell
differentiation and myofiber hypertrophy in transgenic mice. J Biol
Chem 1995; 270: 12109-16.
47 Coolican SA, Samuel DS, Ewton DZ,
McWade FJ, Florini JR. The mitogenic and myogenic actions
of insulin-like growth factors utilize distinct signaling pathways.
J Biol Chem 1997; 272: 6653-62.
48 Chakravarthy MV, Abraha TW, Schwartz RJ,
Fiorotto ML, Booth FW. Insulin-like growth factor-I
extends in vitro replicative life span of skeletal muscle satellite
cells by enhancing G1/S cell cycle progression via the activation
of phosphatidylinositol 3’-kinase/Akt signaling pathway. J Biol
Chem 2000; 275: 35942-52.
49 Musaro A, McCullagh K, Paul A,
Houghton L, Dobrowolny G, Molinaro M, et al.
Localized Igf-1 transgene expression sustains hypertrophy and
regeneration in senescent skeletal muscle. Nat Genet 2001; 27:
195-200.
50 Fiorotto ML, Schwartz RJ, Delaughter MC.
Persistent IGF-I overexpression in skeletal muscle transiently
enhances DNA accretion and growth. FASEB J 2003; 17: 59-60.
51 Ohanna M, Sobering AK, Lapointe T,
Lorenzo L, Praud C, Petroulakis E, et al.
Atrophy of S6K1(-/-) skeletal muscle cells reveals distinct mTOR
effectors for cell cycle and size control. Nat Cell Biol 2005; 7:
286-94.
52 Rommel C, Clarke BA, Zimmermann S,
Nunez L, Rossman R, Reid K, et al.
Differentiation stage-specific inhibition of the Raf-MEK-ERK
pathway by Akt. Science 1999; 286: 1738-41.
53 Tureckova J, Wilson EM, Cappalonga JL,
Rotwein P. Insulin-like growth factor-mediated muscle
differentiation: collaboration between phosphatidylinositol
3-kinase-Akt-signaling pathways and myogenin. J Biol Chem 2001;
276: 39264-70.
54 Accili D. A kinase in the life of the beta cell. J Clin
Invest 2001; 108: 1575-6.
55 Rommel C, Bodine SC, Clarke BA,
Rossman R, Nunez L, Stitt TN, et al. Mediation
of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR
and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol 2001; 3: 1009-13.
56 Bodine SC, Stitt TN, Gonzalez M,
Kline WO, Stover GL, Bauerlein R, et al.
Akt/mTOR pathway is a crucial regulator of skeletal muscle
hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol
2001; 3: 1014-9.
57 Pallafacchina G, Calabria E, Serrano AL,
Kalhovde JM, Schiaffino S. A protein kinase B-dependent
and rapamycin-sensitive pathway controls skeletal muscle growth but
not fiber type specification. Proc Natl Acad Sci USA 2002; 99:
9213-8.
58
Lai KMGonzalez MPoueymirou WTKline WONa E,
Zlotchenko E, et al. Conditional activation of akt in
adult skeletal muscle induces rapid hypertrophy. Mol Cell Biol
2004; 24: 9295-304.
59 Sandri M, Sandri C, Gilbert A, Skurk C,
Calabria E, Picard A, et al. Foxo transcription
factors induce the atrophy-related ubiquitin ligase atrogin-1 and
cause skeletal muscle atrophy. Cell 2004; 117: 399-412.
60 Stitt TN, Drujan D, Clarke BA, Panaro F,
Timofeyva Y, Kline WO, et al. The IGF-1/PI3K/Akt
pathway prevents expression of muscle atrophy-induced ubiquitin
ligases by inhibiting FOXO transcription factors. Mol Cell 2004;
14: 395-403.
61 Kozma SC, Ferrari S, Bassand P,
Siegmann M, Totty N, Thomas G. Cloning of the
mitogen-activated S6 kinase from rat liver reveals an enzyme of the
second messenger subfamily. Proc Natl Acad Sci USA 1990; 87:
7365-9.
62 Raught B, Peiretti F, Gingras AC,
Livingstone M, Shahbazian D, Mayeur GL, et al.
Phosphorylation of eucaryotic translation initiation factor 4B
Ser422 is modulated by S6 kinases. EMBO J 2004; 23: 1761-9.
63 Wang X, Li W, Williams M, Terada N,
Alessi DR, Proud CG. Regulation of elongation factor 2
kinase by p90(RSK1) and p70 S6 kinase. EMBO J 2001; 20: 4370-9.
64 Richardson CJ, Broenstrup M, Fingar DC,
Julich K, Ballif BA, Gygi S, et al. SKAR is a
specific target of S6 kinase 1 in cell growth control. Curr Biol
2004; 14: 1540-9.
65 Holz MK, Ballif BA, Gygi SP, Blenis J.
mTOR and S6K1 mediate assembly of the translation preinitiation
complex through dynamic protein interchange and ordered
phosphorylation events. Cell 2005; 123: 569-80.
66 Jefferies HB, Reinhard C, Kozma SC,
Thomas G. Rapamycin selectively represses translation of the
"polypyrimidine tract" mRNA family. Proc Natl Acad Sci USA 1994;
91: 4441-5.
67 Bodine SC, Latres E, Baumhueter S,
Lai VK, Nunez L, Clarke BA, et al.
Identification of ubiquitin ligases required for skeletal muscle
atrophy. Science 2001; 294: 1704-8.
68 Gomes MD, Lecker SH, Jagoe RT, Navon A,
Goldberg AL. Atrogin-1, a muscle-specific F-box protein highly
expressed during muscle atrophy. Proc Natl Acad Sci USA 2001; 98:
14440-5.
69 Lecker SH, Jagoe RT, Gilbert A, Gomes M,
Baracos V, Bailey J, et al. Multiple types of
skeletal muscle atrophy involve a common program of changes in gene
expression. FASEB J 2004; 18: 39-51.
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