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 | Substrate Phosphory lation Site (Human) | PubMed ID # | Substrate Function and Effect of Phosphorylation |
|---|---|---|---|
| 14-3-3 ζ | S58 | 11956222 | adaptor/ scaffolding protein; controls protein activity through binding to phospho-serine containing proteins; phosphorylation disrupts binding |
| Acinus | S1180 | 16177823 | induces chromatin condensation during apoptosis; phosphorylation inhibits this process |
| ADRB2 | S346 | 11809767 | GPCR; insulin stimulates phosphorylation by Akt and sequestering of β2-adrenergic receptors |
| APS | S598 | 16141217 | adaptor protein; recruited to the insulin receptor to signal insulin-stimulated glucose transport; phosphorylation promotes membrane localization |
| AR (Androgen Receptor) | S213, S791 | 11404460, 11156376 | nuclear receptor; phosphorylation suppresses AR activation, expression of AR target genes and AR-mediated apoptosis |
| A-Raf | S214 | 16170185 | signaling intermediate in Erk1/2 pathway; phosphorylation causes inhibition |
| Arfaptin 2 | S260 | 15809304 | protein levels are elevated in Huntington’s Disease; phosphorylation inhibits polyQ-Huntingtin induced neurotoxicity; promotes cell survival and neuroprotection |
| ASK1 | S83 | 11154276, 14500571, 15911620 | MAPKKK; induces apoptosis via JNK pathway; phosphorylation inhibits activity and promotes survival |
| Ataxin-1 | S776 | 12757707, 17540008 | 14-3-3 binds to and stabilizes ataxin-1, which forms polyglutamine aggregates and neurodegeneration; Akt phosphorylation promotes 14-3-3 binding |
| Bad | S75, S99, S118 | 9381178, 11723239, 9346240, 10949026 | pro-apoptotic protein; phosphorylation inhibits function and promotes survival |
| Bax | S184 | 14766748 | pro-apoptotic protein; phosphorylation sequesters Bax in the cytoplasm and promotes survival |
| Bcl-10 | S218, S231 | 16280327 | pro-apoptotic protein; phosphorylation regulates cellular location and association with Bcl-3 |
| Bim | S87 | 16282323 | pro-apoptotic protein; phosphorylation promotes 14-3-3 binding/inactivation and cell survival |
| B-Raf | S365, S429 | 10869359 | signaling intermediate in Erk1/2 pathway; phosphorylation causes inhibition |
| BRCA1 | T509 | 10542266 | breast cancer susceptibility gene product, tumor suppressor; phosphorylation alters function, perhaps by preventing nuclear localization |
| BRF1 | S92, S203 | 17030608, 15538381 | regulates mRNA decay; phosphorylation causes 14-3-3 binding and inhibits activity |
| CACNB2 | S630 | 15311280 | voltage-dependent calcium channel; phosphorylation regulates channel trafficking to plasma membrane |
| CaRHSP1 | S52 | 15910284 | RNA binding protein; effect of phosphorylation currently unknown |
| Caspase-9 | S196 | 9812896 | protease, initiates apoptosis; phosphorylation inhibits protease activity |
| CENTB1 (ACAP1) | S554 | 16256741 | GTPase-activating protein (GAP) for ARF proteins; phosphorylation prevents recycling of β1-integrin containing endosomes and cell migration |
| Chk1 | S280 | 15107605, 12062056 | DNA damage effector; regulates G2/M transition during DNA damage; phosphorylation inhibits function by preventing phosphorylation by ATM/ATR |
| Cot (Tpl2) | S400 | 12138205 | oncogene; phosphorylation induces NF-κB-dependent transcription |
| CREB | S133 | 9829964 | transcription factor; phosphorylation promotes CBP co-activator recruitment and increased expression of cell survival genes |
| CSP | S10 | 16243840 | exocytosis; phosphorylation regulates the kinetics of late stage exocytosis |
| CTNNB1 (β-Catenin) | S552 | 17237784 | Wnt signaling pathway protein; phosphorylation causes nuclear localization |
| CTNND2 (Catenin δ-2) | T457 | 17993462 | phosphorylation promotes binding to p190RhoGEF, dendritic morphogenesis |
| Connexin 43 | S372 | 17008717 | gap junction protein; phosphorylation allows for 14-3-3 binding to occur |
| DLC1 (p122RhoGAP) | S329 | 16338927 | tumor suppressor and insulin stimulated phosphoprotein; may play role in Glut4 translocation; phosphorylation may inhibit its GAP activity |
| EDG-1 | T236 | 11583630 | GPCR; phosphorylation activates signaling to promote cell migration |
| eNOS | S1176 | 10376602, 10376603, 10514497 | phosphorylation results in enzyme activation and NO production; cardiovascular homeostasis (vasodilation, vascular remodeling, angiogenesis) |
| ER-α (Estrogen Receptor-α) | S167 | 11139588, 16113102 | nuclear receptor and transcription factor; phosphorylation activates the receptor and increases gene expression causing mammary and uterine cell proliferation |
| Ezh2 | S21 | 16224021 | phosphorylation decreases histone H3 methylation of Lys27; phosphorylation increases gene expression |
| Ezrin | T567 | 15531580 | phosphorylation promotes actin binding and cytoskeletal organization |
| FoxO1a | T24, S256, S319 | 10358075, 10377430, 11237865 | transcription factor involved in cell cycle arrest, apoptosis and glucose metabolism; phosphorylation causes export from the nucleus and inhibits activity |
| FoxO3a | T32, S253 | 11154281, 10102273 | transcription factor involved in cell cycle arrest and apoptosis; phosphorylation causes export from the nucleus and inhibits activity |
| FoxO4 | T32, S197, S262 | 11313479, 10217147, 14690436 | transcription factor involved in cell cycle arrest, apoptosis and insulin signaling; phosphorylation causes export from the nucleus and inhibits activity |
| Gab2 | S159 | 11782427 | docking/scaffolding protein; proto-oncogene; RTK signaling intermediate; phosphorylation inhibits activity |
| GABRB2 | S434 | 12818177 | ligand gated chloride ion channel; phosphorylation increases synaptic transmission |
| GATA-1 | S310 | 16107690 | transcription factor; phosphorylation increases activity and promotes blood cell differentiation |
| GATA-2 | S401 | 15837948 | transcription factor; phosphorylation inhibits activity to promote adipogenesis and reduce inflammation |
| Girdin | S1417 | 16139227 | actin binding protein; phosphorylation promotes cell migration |
| Grb10 | S428 | 15722337 | adaptor protein and RTK signaling intermediate; phosphorylation allows 14-3-3 binding |
| GSK-3α | S21 | 11520785, 8524413 | cell cycle, glycogen synthesis and apoptosis; phosphorylation inhibits activity |
| GSK-3β | S9 | 12095987, 12900420, 15073173 | cell cycle, glycogen synthesis and apoptosis; phosphorylation inhibits activity |
| H3.3 (Histone H3) | S10 | 12529330 | phosphorylation promotes chromosome condensation and remodeling |
| HSP27 | S82 | 12740362 | apoptosis; molecular chaperone; phosphorylation results in HSP27 dissociation from Akt |
| HtrA2 | S212 | 17311912 | protease released during apoptosis; phosphorylation inhibits activity and attenuates its pro-apoptotic function |
| Huntingtin | S421 | 12062094, 15843398 | Huntington’s Disease; Akt phosphorylation blocks nuclear aggregation and provides neuroprotection |
| IKK-α | T23 | 10485710 | phosphorylation activates NF-κB; immune/stress response |
| IP3R1 | S2690 | 16332683 | Ca2+ release and signaling; phosphorylation induces resistance to apoptosis, possibly through caspase-3 inactivation |
| IRAK1 | T100 | 11976320 | IL-1 induced NF-κB activation; phosphorylation inhibits activity |
| IRS-1 | S527 | 17579213 | insulin receptor signaling intermediate; phosphorylation inhibits function |
| KHSRP | S193 | 17177604 | promotes mRNA degradation; phosphorylation inhibits function |
| MDM2 | S166, S186, S188 | 11504915, 15169778, 11850850 | ubiquitin ligase involved in p53 degradation; phosphorylation results in translocation to the nucleus and inhibition of p53 |
| MLK3 | S674 | 12458207 | JNK-mediated neuronal cell death; phosphorylation inhibits activity |
| mTOR | S2448 | 10567225, 15208671 | protein synthesis and cell growth; phosphorylation increases activity |
| Myt1 | S83 | 11802161 | Wee1 family member and cell cycle regulator; phosphorylation downregulates Myt1 and initiates M-phase |
| Ndrg2 | T348 | 14985363 | insulin-stimulated phosphoprotein; phosphorylation promotes insulin signaling |
| NuaK1 | S600 | 12409306 | AMPK family member activated under nutrient starvation; mediates cell survival during glucose starvation; phosphorylation increases kinase activity |
| Nur77 | S351 | 11274386, 11438550 | nuclear receptor, transcription factor; T cell apoptosis; phosphorylation inhibits transcriptional activity |
| p21 Waf1/Cip1 | T144, S145 | 11756412, 11231573, 15173090 | regulates cell cycle and cell survival; phosphorylation increases protein stability |
| p27 Kip1 | S10, T157, T198 | 12042314, 14504289, 12244303 | negative regulator of the cell cycle; phosphorylation causes 14-3-3 binding, cytoplasmic localization and allows cell cycle progression |
| p300 | S1834 | 11116148, 16024795 | transcriptional co-activator; phosphorylation can either activate or suppress transcriptional activity depending on cell type and physiological stimuli |
| p47phox | S304, S328 | 12734380 | component of NADPH oxidase complex; phosphorylation promotes respiratory burst activity in human neutrophils |
| PAK1 | S21 | 14585966 | cytoskeletal signaling; phosphorylation activates PAK1 and promotes cell migration |
| PAWR | S257 | 16209943 | phosphorylation leads to inhibition of apoptosis |
| PDCD4 | S67, S457 | 16357133 | tumor suppressor protein that is strongly induced during apoptosis; phosphorylation inhibits tumor suppressor function |
| PDE3A | S292, S293, S294 | 17124499 | regulates levels of cAMP and cGMP; insulin-dependent oocyte maturation; phosphorylation increases activity |
| PDE3B | S295 | 10454575 | regulates levels of cAMP and cGMP; activated by insulin to regulate lipolysis; phosphorylation increases activity |
| PEA-15 | S116 | 12808093 | anti-apoptotic protein; phosphorylation increases protein activity and stability |
| Peripherin | S59 | 17569669 | neuronal intermediate filament protein; phosphorylation promotes motor nerve regeneration |
| PFKFB2 | S466, S483 | 9211863, 10521487, 16829026 | glycolytic enzyme; insulin-mediated glucose metabolism; phosphorylation increases activity |
| PFKFB3 | S461 | 15896703 | phosphorylation regulates enzymatic activation |
| PGC-1 | S571 | 17554339 | regulates gluconeogenesis and fatty acid oxidation; phosphorylation inhibits function |
| PIP5K (PIKfyve) | S307 | 15546921 | phosphorylation promotes insulin-stimulated Glut4 trafficking |
| PLCγ1 | S1248 | 16525023 | catalyzes PI 4,5 bisphosphate to IP3 and DAG; increases intracellular Ca2+ levels; phosphorylation increases activity and enhances EGF-stimulated cell motility |
| PRAS40 (Akt1S1) | T246 | 12524439 | binds to and inhibits mTOR; phosphorylation causes 14-3-3 binding/inhibition and results in increased protein synthesis |
| PRPK | S250 | 17712528 | phosphorylation causes activation of PRPK kinase, resulting in p53 phosphorylation |
| PTP1B | S50 | 11579209 | protein tyrosine phosphatase that dephosphorylates the insulin receptor; phosphorylation inhibits activity |
| QIK | S358 | 17805301 | AMPK related protein; phosphorylation leads to kinase activation and promotes ubiquitination/degradation of TORC2 |
| Rac1 | S71 | 10617634 | Rho-GTPase; actin cytoskeletal organization; phosphorylation inhibits GTP-binding activity |
| Raf1 (c-Raf) | S259 | 11443134, 12087097 | signaling intermediate in Erk1/2 pathway; phosphorylation inhibits activity |
| RARα | S96 | 16417524 | nuclear receptor transcription factor; phosphorylation inhibits transactivation |
| Ron | S1394 | 12919677, 14505491 | RTK for macrophage stimulating protein (MSP); cell adhesion, proliferation and migration; phosphorylation causes 14-3-3 binding |
| S6 | S235, S236 | 12151408, 15358595 | S6 ribosomal protein; phosphorylation activates the protein and promotes protein synthesis |
| SEK1 | S80 | 11707464, 15911620 | signaling intermediate of the JNK/SAPK pathway; stress/inflammation; phosphorylation inhibits activity |
| SH3MD2 | S472 | 17535800 | phosphorylation prevents binding to RACK1 and apoptosis |
| STXBP4 | S99 | 15753124 | phosphorylation regulates intracellular location and binding to Glut4 and STX4, which allows plasma membrane fusion of Glut4 vesicles |
| SYTL1 (JFC1) | S241 | 15998322 | phosphorylation allows Rab27a binding and vesicle secretion |
| TAL-1 | T90 | 15930267 | transcription factor; phosphorylation inhibits transcriptional repressor activity; regulates intracellular localization |
| TBC1D1 | T596 | 18276596 | insulin stimulated Rab GTPase-activating protein; structurally and functionally similar to AS160 |
| TBC1D4 (AS160) | T642, T649 | 11994271, 16880201 16935857 | Rab GTPase-activing protein involved in insulin-stimulated Glut4 trafficking; phosphorylation promotes glucose transport |
| Tuberin (TSC2) | S939, S981, T1462 | 12150915, 12172553 15342917, 16636147 | tumor suppressor that inhibits mTOR; phosphorylation inhibits function and allows protein synthesis to occur |
| USP8 | T945 | 17210635 | deubiquitinating enzyme that plays a role in growth factor receptor trafficking and degradation; phosphorylation increases protein stability |
| VCP | S351, S745, S747 | 16551632 | ATPase and molecular chaperone; phosphorylation may impair its pro-apoptotic effects and promote cell survival |
| Wee1 | S642 | 15964826 | cell cycle regulator; phosphorylation causes 14-3-3 binding and promotes cell cycle progression |
| WNK1 | T60 | 14611643, 16081417 | regulates ion channels; phosphorylation of WNK1 causes SGK1 activation and regulation of sodium ion transport |
| XIAP | S87 | 14645242 | inhibitor of apoptosis; phosphorylation prevents ubiquitination/degradation and causes increased cell survival |
| YAP1 | S127 | 12535517 | transcriptional co-activator; phosphorylation causes 14-3-3 binding and inhibits pro-apoptotic gene expression |
| YB1 | S102 | 15806160 | regulates transcription by binding to Y-box promoter sequences; phosphorylation causes nuclear translocation and activation |
| Zyxin | S142 | 17572661 | pro-survival focal adhesion molecule; phosphorylation causes nuclear localization and suppression of apoptosis |
created October 2008
