Cell Signaling Technology

PI3K / Akt Substrates

The PI3K / Akt Substrates Table provides a comprehensive list of demonstrated downstream targets of Akt phosphorylation, along with the relevant phosphorylation site, publication reference and effect of phosphorylation. This information was generated using PhosphoSitePlus®, CST’s open scientific resource of protein modification information, available on the web at www.phosphosite.org.

Substrate Isoform Substrate Site (Human) Substrate Function and Effect of Phosphorylation References
Acinus 1 S1180 induces chromatin condensation during apoptosis; phosphorylation inhibits this process (1)
APS 1 S598 adaptor protein; recruited to the insulin receptor to signal insulin-stimulated glucose transport; phosphorylation promotes membrane localization (2)
AR (Androgen Receptor) 1 S213, S791 nuclear receptor; phosphorylation suppresses AR activation, expression of AR target genes, and AR-mediated apoptosis (3, 4)
Arfaptin 2 1 S260 protein levels are elevated in Huntington’s Disease; phosphorylation inhibits polyQ-Huntingtin induced neurotoxicity; promotes cell survival and neuroprotection (5)
AS160 1 S588, T642 insulin stimulated Rab GTPase-activating protein, structurally and functionally similar to TBC1D1; phosphorylation results in increased GLUT4 translocation (6)
ASK1 1, 2 S83 MAPKKK; induces apoptosis via JNK pathway; phosphorylation inhibits activity and promotes survival (7, 8, 9)
Ataxin-1 1 S776 14-3-3 binds to and stabilizes ataxin-1, which forms polyglutamine aggregates and neurodegeneration; phosphorylation promotes 14-3-3 binding (10, 11)
Bad 1 S75, S99, S118 pro-apoptotic protein; phosphorylation inhibits function and promotes survival (12, 13, 14, 15)
Bcl-xL 1 S106 prevent apoptosis through binding to apoptotic protein; phosphorylation promotes VDAC binding (16)
Bim 1 S87 pro-apoptotic protein; phosphorylation promotes 14-3-3 binding/inactivation and cell survival (17)
B-Raf 1, 3 S365, S429 signaling intermediate in Erk1/2 pathway; phosphorylation causes inhibition (18)
BRCA1 1 T509 breast cancer susceptibility gene product, tumor suppressor; phosphorylation alters function, perhaps by preventing nuclear localization (19)
CACNB2 1 S630 voltage-dependent calcium channel; phosphorylation regulates channel trafficking to plasma membrane (20)
CaRHSP1 1 S52 RNA binding protein; phosphorylation effect currently unknown (21)
Caspase-9 1 S196 protease, initiates apoptosis; phosphorylation inhibits protease activity (22)
CBP 1 T1871 acetylates histone and non-histone proteins; phosphorylation increases activity (23)
CCT2 1 S260 member of protein chaperone complex; effect of phosphorylation currently unknown (24)
Cdc25B 1 S353 protein phosphatase responsible for cdc2 activation; phosphorylation promotes activation of M-phase promoting factor (25)
CDK2 1 T39 cyclin-dependent kinase functioning in S-phase; phosphorylation increases cyclin A binding (26)
CENTB1 (ACAP1) 1 S554 GTPase-activating protein (GAP) for ARF proteins; phosphorylation prevents recycling of b1-integrin containing endosomes and cell migration (27)
Chk1 1 S280 DNA damage effector; regulates G2/M transition during DNA damage; phosphorylation inhibits function by preventing phosphorylation by ATM/ATR (28, 29)
CK1-D 1 S370 kinase and core component of circadian clock; phosphorylation inhibits kinase activity (30)
Connexin 43 1, 2 S372 gap junction protein; phosphorylation allows 14-3-3 binding (31)
Cot (Tpl2) 1 S400 oncogene; phosphorylation induces NF-kB-dependent transcription (32)
CSP 1 S10 exocytosis; phosphorylation regulates the kinetics of late stage exocytosis (33)
CTNNB1 (b-Catenin) 1, 2 S552 Wnt signaling pathway protein; phosphorylation causes nuclear localization (34)
CTNND2 (Catenin d-2) 1 T457 transcriptional activator, plays a role in adhesion molecule regulation; phosphorylation promotes binding to p190RhoGEF, dendritic morphogenesis (35)
CUGBP1 1 S28 RNA-binding protein; phosphorylation enhances interaction with cyclin D1 mRNA (36)
DLC1 (p122RhoGAP) 1 S329 tumor suppressor and insulin stimulated phosphoprotein; may play role in Glut4 translocation; phosphorylation may inhibit its GAP activity (37)
EDC3 2 S161 involved in removal of the mRNA 5’ cap structure; phosphorylation induces 14-3-3 protein interaction and promotes ED3 mediated post-transcriptional regulation through mRNA (38)
EDG-1 1 T236 G protein-coupled receptor; phosphorylation activates signaling to promote cell migration (39)
eIF4B 1 S422 necessary for binding of mRNA to ribosomes; phosphorylation increases transcriptional activity (40)
eNOS 1 S1176 enzyme that catalyzes the production of nitric oxide (NO); phosphorylation results in enzyme activation, NO production, and cardiovascular homeostasis (vasodilation, vascular remodeling, angiogenesis) (41, 42, 43)
ER-a (Estrogen Receptor-a) 1, 2 S167 nuclear receptor and transcription factor; phosphorylation activates the receptor and increases gene expression, causing mammary and uterine cell proliferation (44, 45)
Ezh2 1 S21 methyltransferase; phosphorylation decreases histone H3 methylation of Lys27 and increases gene expression (46)
Ezrin 2 T567 plasma membrane/cytoskeletal linker protein; phosphorylation promotes actin binding and cytoskeletal organization (47)
FANCA 1 S1149 ATPase involved in DNA repair; phosphorylation is negatively regulated by Akt (48)
FLNC 1, 2 S2233 muscle-specific filamin functioning in muscle cells; phosphorylation effect currently unknown (49)
FOXA2 1 T156 transcription factor involved in embryonic development and differentiation; phosphorylation results in nuclear exclusion and inhibition of FoxA2-dependent transcriptional activity (50)
FOXG1 1 T279 transcriptional repression factor involved in brain development; phosphorylation promotes nuclear export (51)
FoxO1a 1 T24, S256, S319 transcription factor involved in cell cycle arrest, apoptosis, and glucose metabolism; phosphorylation causes export from the nucleus and inhibits activity (52, 53, 54)
FoxO3a 1 T32, S253 transcription factor involved in cell cycle arrest and apoptosis; phosphorylation causes export from the nucleus and inhibits activity (55, 56)
FoxO4 1 T32, S197, S262 transcription factor involved in cell cycle arrest, apoptosis, and insulin signaling; phosphorylation causes export from the nucleus and inhibits activity (57, 58, 59)
Gab2 1 S159 docking/scaffolding protein; proto-oncogene; RTK signaling intermediate; phosphorylation inhibits activity (60)
GATA-1 1 S310 transcription factor; phosphorylation increases activity and promotes blood cell differentiation (61)
GATA-2 1 S401 transcription factor; phosphorylation inhibits activity to promote adipogenesis and reduce inflammation (62)
Girdin 1 S1417 actin binding protein; phosphorylation promotes cell migration (63)
GOLGA3 1 S174, S389 golgi auto-antigen; phosphorylation results in reduced apoptosis (64)
GSK-3a 1 S21 cell cycle, glycogen synthesis, and apoptosis; phosphorylation inhibits activity (65, 66)
GSK-3b 1 S9 cell cycle, glycogen synthesis, and apoptosis; phosphorylation inhibits activity (67, 68, 69)
H2B 1 S37 core component of the nucleosome; phosphorylation effect currently unknown (70)
HMOX1 1 S188 heme oxigenase involved in stress response; phosphorylation regulates binding affinity (71)
hnRNP A1 1 S199 involved in pre-mRNA packaging into hnRNP particles and transport of poly(A) mRNA from cytoplasm to nucleus; phosphorylation regulates role in cyclin D1 and c-Myc IRES activity (72)
hnRNP E1 1, 2 S43 binds to single-stranded nucleic acid; phosphorylation results in disruption of BAT element binding and translational activation of Dab2 and ILEI mRNA (73)
HtrA2 1, 2 S212 protease released during apoptosis; phosphorylation inhibits activity and attenuates its pro-apoptotic function (74)
Huntingtin 1 S421 Huntington’s Disease; Akt phosphorylation blocks nuclear aggregation and provides neuroprotection (75, 76)
IKK-a 1, 2 T23 NF-kB signaling intermediate; phosphorylation activates NF-kB and immune/stress response (77)
IP3R1 1 S2690 Ca2+ release and signaling; phosphorylation induces resistance to apoptosis, possibly through caspase-3 inactivation (78)
IRS-1 1 S527 insulin receptor signaling intermediate; phosphorylation inhibits function (79)
Kv11.1 iso5 1 T897 pore-forming subunit of voltage-gated potassium channels, essential for rhythmic excitability of cardiac muscle and endocrine cells; phosphorylation inhibits channels (80)
Lamin A/C 1 S301, S404 component of nuclear lamina; phosphorylation regulates function of nuclear lamina (81)
Mad1 1 S145 component of spindle-assembly checkpoint; phosphorylation results in ubiquitination and degradation through 26S proteasome pathway (82, 83)
MDM2 1 S166, S186, S188 ubiquitin ligase involved in p53 degradation; phosphorylation results in translocation to the nucleus and inhibition of p53 (84, 85, 86)
MLK3 1 S674 JNK-mediated neuronal cell death; phosphorylation inhibits activity (87)
METTL1 1 S27 catalyzes the formation of m7G46 in tRNA; phosphorylation results in inactivation (88)
MST1 1 T120 pro-apoptotic kinase; phosphorylation inhibits kinase activity and nuclear translocation resulting in inhibition of pro-apoptotic signaling (89)
mTOR 1 S2448 protein synthesis and cell growth; phosphorylation increases activity (90, 91)
MYO5A 2 S1652 actin-based motor protein with a role in cytoplasmic vesicle transport and anchorage; phosphorylation promotes insulin-mediated glut4 vesicle translocation (92)
Myt1 1 S83 Wee1 family member and cell cycle regulator; phosphorylation downregulates Myt1 and initiates M-phase (93)
Ndrg2 1 T348 insulin-stimulated phosphoprotein; phosphorylation promotes insulin signaling (94)
NFAT90 1 S647 translation inhibitory protein; phosphorylation required for nuclear export (95)
NMDAR2C 1 S1081 Glutamate receptor channel subunit; phosphorylation promotes binding to 14-3-3e and leads to increased surface expression of cerebellar NMDA receptors (96)
NuaK1 1 S600 AMPK family member activated under nutrient starvation; mediates cell survival during glucose starvation; phosphorylation increases kinase activity (97)
Nur77 1 S351 nuclear receptor, transcription factor; T cell apoptosis; phosphorylation inhibits transcriptional activity (98, 99)
p21 Waf1/Cip1 1 T144, S145 regulates cell cycle and cell survival; phosphorylation increases protein stability (100, 101, 102)
p300 1 S1834 transcriptional co-activator; phosphorylation can either activate or suppress transcriptional activity depending on cell type and physiological stimuli (103, 104)
Palladin 1 S507 actin-bundling protein; phosphorylation promotes F-actin bundling and inhibits cell migration (105)
PDCD4 1 S67, S457 tumor suppressor protein that is strongly induced during apoptosis; phosphorylation inhibits tumor suppressor function (106)
PDE3A 1 S292, S293, S294 regulates levels of cAMP and cGMP; insulin-dependent oocyte maturation; phosphorylation increases activity (107)
PDE3B 1 S295 regulates levels of cAMP and cGMP; activated by insulin to regulate lipolysis; phosphorylation increases activity (108)
Peripherin 1 S59 neuronal intermediate filament protein; phosphorylation promotes motor nerve regeneration (109)
PFKFB2 1 S466, S483 glycolytic enzyme; insulin-mediated glucose metabolism; phosphorylation increases activity (110, 111, 112)
PGC-1 1, 2 S571 regulates gluconeogenesis and fatty acid oxidation; phosphorylation inhibits function (113)
PLCg1 1 S1248 catalyzes PI 4,5 bisphosphate to IP3 and DAG; increases intracellular Ca2+ levels; phosphorylation increases activity and enhances EGF-stimulated cell motility (114)
PRAS40 (Akt1S1) 1 T246 binds to and inhibits mTOR; phosphorylation causes 14-3-3 binding/inhibition and results in increased protein synthesis (115)
PRPK 1 S250 p53 binding protein and kinase; phosphorylation causes activation and results in p53 phosphorylation (116)
PTP1B 1 S50 protein tyrosine phosphatase that dephosphorylates the insulin receptor; phosphorylation inhibits activity (117)
QIK 2 S358 AMPK related protein; phosphorylation leads to kinase activation and promotes ubiquitination/degradation of TORC2 (118)
Rac1 1 S71 Rho-GTPase; actin cytoskeletal organization; phosphorylation inhibits GTP-binding activity (119)
Raf1 (c-Raf) 1 S259 signaling intermediate in Erk1/2 pathway; phosphorylation inhibits activity (120, 121)
RANBP3 1 S126 RAN binding protein 3 functions in nuclear transport; phosphorylation mediates Ran binding and regulates nuclear transport (122)
Ron 1 S1394 receptor tyrosine kinase for macrophage stimulating protein (MSP); cell adhesion, proliferation and migration; phosphorylation causes 14-3-3 binding (123, 124)
S6 1, 2 S235, S236 S6 ribosomal protein; phosphorylation activates the protein and promotes protein synthesis (125, 126)
SEK1 1 S80 signaling intermediate of the JNK/SAPK pathway; stress/inflammation; phosphorylation inhibits activity (127, 9)
SH3BP4 1 S246 controls selective internalization of the transferrin receptor through endocytosis; phosphorylation promotes 14-3-3 binding at the plasma membrane (128)
SH3RF1 1, 2 S304 scaffolding protein that binds to activated Rac and promotes apoptosis via JNK activation; phosphorylation reduces ability to bind Rac, promoting apoptosis (129)
Skp2 1 S72 component of SCF-Skp2 E3 ubiquitin ligase complex; phosphorylaion regulates Skp2 stability and cytoplasmic localization (130)
SKI 1 T458 negative regulator of TGF-b signaling by binding to Smads; phosphorylation causes its destabilization and reduces Ski-mediated inhibition of expression of Smad7 (131)
SSB 1 T302 RNA binding protein, plays a role in processing of RNA polymerase III transcripts; phosphorylation promotes export to cytoplasm where it binds polysomes and regulates expression of a specific set of mRNAs (132)
TAL-1 1 T90 transcription factor; phosphorylation inhibits transcriptional repressor activity and regulates intracellular localization (133)
TBC1D4 (AS160) 1 T642, T649 Rab GTPase-activating protein involved in insulin-stimulated Glut4 trafficking; phosphorylation promotes glucose transport (6, 134, 135)
TERT 1 S227, S824 telomerase reverse transcriptase, chomosome length maintenance; phosphorylation enhances telomerase activity (136)
TOPBP1 1 S1159 induces a large increase in the kinase activity of ATR; phosphorylation prevents the enhanced association of ATR with TopBP1 after DNA damage (137)
TRF1 1 T273 controls telomere structure; phosphorylation decreases telomere length (138)
TTC3 1 S378 E3 ligase to Akt; phosphorylation promotes TTC3 function, such as ability to ubiquitinylate and destabilize Akt (139)
Tuberin (TSC2) 1 S939, S981, T1462 tumor suppressor that inhibits mTOR; phosphorylation inhibits function and allows protein synthesis to occur (140, 141, 142, 143)
USP8 1 T945 deubiquitinating enzyme that plays a role in growth factor receptor trafficking and degradation; phosphorylation increases protein stability (144)
VCP 1 S351 ATPase and molecular chaperone; phosphorylation may impair its pro-apoptotic effects and promote cell survival (145)
WNK1 1 T60 regulates ion channels; phosphorylation of WNK1 causes SGK1 activation and regulation of sodium ion transport (146, 147)
XIAP 1, 2 S87 inhibitor of apoptosis; phosphorylation prevents ubiquitination/degradation and causes increased cell survival (148)
YAP1 1 S127 transcriptional co-activator; phosphorylation causes 14-3-3 binding and inhibits pro-apoptotic gene expression (149)
YB1 1 S102 regulates transcription by binding to Y-box promoter sequences; phosphorylation causes nuclear translocation and activation (150)
Zyxin 1 S142 pro-survival focal adhesion molecule; phosphorylation causes nuclear localization and suppression of apoptosis (151)

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created October 2008

revised November 2010

Reference