PIP3 activates AKT signaling (Homo sapiens)

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119. Chen SY, Chen HC.; ''Direct interaction of focal adhesion kinase (FAK) with Met is required for FAK to promote hepatocyte growth factor-induced cell invasion.''; PubMed Europe PMC Scholia
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124. Meng Z, Jia LF, Gan YH.; ''PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition.''; PubMed Europe PMC Scholia
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129. Wang W, Chen Y, Wang S, Hu N, Cao Z, Wang W, Tong T, Zhang X.; ''PIASxα ligase enhances SUMO1 modification of PTEN protein as a SUMO E3 ligase.''; PubMed Europe PMC Scholia
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268. Flaswinkel H, Reth M.; ''Dual role of the tyrosine activation motif of the Ig-alpha protein during signal transduction via the B cell antigen receptor.''; PubMed Europe PMC Scholia
269. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC.; ''Regulation of cell death protease caspase-9 by phosphorylation.''; PubMed Europe PMC Scholia
270. Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, Kenche V, Anderson KE, Dopheide SM, Yuan Y, Sturgeon SA, Prabaharan H, Thompson PE, Smith GD, Shepherd PR, Daniele N, Kulkarni S, Abbott B, Saylik D, Jones C, Lu L, Giuliano S, Hughan SC, Angus JA, Robertson AD, Salem HH.; ''PI 3-kinase p110beta: a new target for antithrombotic therapy.''; PubMed Europe PMC Scholia
271. Rameh LE, Tolias KF, Duckworth BC, Cantley LC.; ''A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate.''; PubMed Europe PMC Scholia
272. Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Brush J, Godowski PJ.; ''Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4.''; PubMed Europe PMC Scholia
273. Williams CC, Allison JG, Vidal GA, Burow ME, Beckman BS, Marrero L, Jones FE.; ''The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone.''; PubMed Europe PMC Scholia
274. Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, Schnell C, Guthy D, Nagel T, Wiesmann M, Brachmann S, Fritsch C, Dorsch M, Chène P, Shoemaker K, De Pover A, Menezes D, Martiny-Baron G, Fabbro D, Wilson CJ, Schlegel R, Hofmann F, García-Echeverría C, Sellers WR, Voliva CF.; ''Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor.''; PubMed Europe PMC Scholia
275. Kone BC, Kuncewicz T, Zhang W, Yu ZY.; ''Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide.''; PubMed Europe PMC Scholia
276. Kovacsovics TJ, Bachelot C, Toker A, Vlahos CJ, Duckworth B, Cantley LC, Hartwig JH.; ''Phosphoinositide 3-kinase inhibition spares actin assembly in activating platelets but reverses platelet aggregation.''; PubMed Europe PMC Scholia
277. Law CL, Sidorenko SP, Chandran KA, Draves KE, Chan AC, Weiss A, Edelhoff S, Disteche CM, Clark EA.; ''Molecular cloning of human Syk. A B cell protein-tyrosine kinase associated with the surface immunoglobulin M-B cell receptor complex.''; PubMed Europe PMC Scholia
278. Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM, Zbar B.; ''Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.''; PubMed Europe PMC Scholia
279. Torres J, Pulido R.; ''The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation.''; PubMed Europe PMC Scholia
280. Shinohara H, Kurosaki T.; ''Comprehending the complex connection between PKCbeta, TAK1, and IKK in BCR signaling.''; PubMed Europe PMC Scholia
281. Lamorte L, Royal I, Naujokas M, Park M.; ''Crk adapter proteins promote an epithelial-mesenchymal-like transition and are required for HGF-mediated cell spreading and breakdown of epithelial adherens junctions.''; PubMed Europe PMC Scholia
282. Li N, Zhang Y, Han X, Liang K, Wang J, Feng L, Wang W, Songyang Z, Lin C, Yang L, Yu Y, Chen J.; ''Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth.''; PubMed Europe PMC Scholia
283. Ikenoue T, Inoki K, Zhao B, Guan KL.; ''PTEN acetylation modulates its interaction with PDZ domain.''; PubMed Europe PMC Scholia
284. Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
285. Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C.; ''Scatter factor/hepatocyte growth factor is essential for liver development.''; PubMed Europe PMC Scholia
286. Hammes SR, Levin ER.; ''Extranuclear steroid receptors: nature and actions.''; PubMed Europe PMC Scholia
287. Zhang X, Loijens JC, Boronenkov IV, Parker GJ, Norris FA, Chen J, Thum O, Prestwich GD, Majerus PW, Anderson RA.; ''Phosphatidylinositol-4-phosphate 5-kinase isozymes catalyze the synthesis of 3-phosphate-containing phosphatidylinositol signaling molecules.''; PubMed Europe PMC Scholia
288. Marlin MC, Li G.; ''Biogenesis and function of the NGF/TrkA signaling endosome.''; PubMed Europe PMC Scholia
289. Yang H, Kong W, He L, Zhao JJ, O'Donnell JD, Wang J, Wenham RM, Coppola D, Kruk PA, Nicosia SV, Cheng JQ.; ''MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN.''; PubMed Europe PMC Scholia
290. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB.; ''NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase.''; PubMed Europe PMC Scholia
291. Tan PL, Shavlakadze T, Grounds MD, Arthur PG.; ''Differential thiol oxidation of the signaling proteins Akt, PTEN or PP2A determines whether Akt phosphorylation is enhanced or inhibited by oxidative stress in C2C12 myotubes derived from skeletal muscle.''; PubMed Europe PMC Scholia
292. Ahmed SF, Deb S, Paul I, Chatterjee A, Mandal T, Chatterjee U, Ghosh MK.; ''The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation.''; PubMed Europe PMC Scholia
293. Biswas DK, Singh S, Shi Q, Pardee AB, Iglehart JD.; ''Crossroads of estrogen receptor and NF-kappaB signaling.''; PubMed Europe PMC Scholia
294. Arasada RR, Carpenter G.; ''Secretase-dependent tyrosine phosphorylation of Mdm2 by the ErbB-4 intracellular domain fragment.''; PubMed Europe PMC Scholia
295. Lennartsson J, Rönnstrand L.; ''The stem cell factor receptor/c-Kit as a drug target in cancer.''; PubMed Europe PMC Scholia
296. Marino M, Ascenzi P, Acconcia F.; ''S-palmitoylation modulates estrogen receptor alpha localization and functions.''; PubMed Europe PMC Scholia
297. La Rosa P, Pesiri V, Leclercq G, Marino M, Acconcia F.; ''Palmitoylation regulates 17β-estradiol-induced estrogen receptor-α degradation and transcriptional activity.''; PubMed Europe PMC Scholia
298. Gao T, Furnari F, Newton AC.; ''PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth.''; PubMed Europe PMC Scholia
299. Song LB, Li J, Liao WT, Feng Y, Yu CP, Hu LJ, Kong QL, Xu LH, Zhang X, Liu WL, Li MZ, Zhang L, Kang TB, Fu LW, Huang WL, Xia YF, Tsao SW, Li M, Band V, Band H, Shi QH, Zeng YX, Zeng MS.; ''The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells.''; PubMed Europe PMC Scholia
300. Zeng F, Xu J, Harris RC.; ''Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells.''; PubMed Europe PMC Scholia
301. Crosier PS, Ricciardi ST, Hall LR, Vitas MR, Clark SC, Crosier KE.; ''Expression of isoforms of the human receptor tyrosine kinase c-kit in leukemic cell lines and acute myeloid leukemia.''; PubMed Europe PMC Scholia
302. Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H, Pavletich NP, Carver BS, Cordon-Cardo C, Erdjument-Bromage H, Tempst P, Chi SG, Kim HJ, Misteli T, Jiang X, Pandolfi PP.; ''Ubiquitination regulates PTEN nuclear import and tumor suppression.''; PubMed Europe PMC Scholia
303. Schaeper U, Gehring NH, Fuchs KP, Sachs M, Kempkes B, Birchmeier W.; ''Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses.''; PubMed Europe PMC Scholia
304. Shenoy SS, Nanda H, Lösche M.; ''Membrane association of the PTEN tumor suppressor: electrostatic interaction with phosphatidylserine-containing bilayers and regulatory role of the C-terminal tail.''; PubMed Europe PMC Scholia
305. Kim YJ, Sekiya F, Poulin B, Bae YS, Rhee SG.; ''Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2.''; PubMed Europe PMC Scholia
306. 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.''; PubMed Europe PMC Scholia
307. Slavik JM, Hutchcroft JE, Bierer BE.; ''CD28/CTLA-4 and CD80/CD86 families: signaling and function.''; PubMed Europe PMC Scholia
308. Das S, Dixon JE, Cho W.; ''Membrane-binding and activation mechanism of PTEN.''; PubMed Europe PMC Scholia
309. Uygur B, Abramo K, Leikina E, Vary C, Liaw L, Wu WS.; ''SLUG is a direct transcriptional repressor of PTEN tumor suppressor.''; PubMed Europe PMC Scholia
310. Sweeney C, Lai C, Riese DJ, Diamonti AJ, Cantley LC, Carraway KL.; ''Ligand discrimination in signaling through an ErbB4 receptor homodimer.''; PubMed Europe PMC Scholia
311. Letourneux C, Rocher G, Porteu F.; ''B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK.''; PubMed Europe PMC Scholia
312. Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, Kim WJ, Okimoto RA, Bell DW, Sgroi DC, Christensen JG, Settleman J, Haber DA.; ''Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752.''; PubMed Europe PMC Scholia
313. Voncken JW, Niessen H, Neufeld B, Rennefahrt U, Dahlmans V, Kubben N, Holzer B, Ludwig S, Rapp UR.; ''MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1.''; PubMed Europe PMC Scholia
314. Huh CG, Factor VM, Sánchez A, Uchida K, Conner EA, Thorgeirsson SS.; ''Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair.''; PubMed Europe PMC Scholia
315. Poo MM.; ''Neurotrophins as synaptic modulators.''; PubMed Europe PMC Scholia
316. Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP.; ''FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics.''; PubMed Europe PMC Scholia
317. Rudd CE, Schneider H.; ''Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling.''; PubMed Europe PMC Scholia
318. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T.; ''MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer.''; PubMed Europe PMC Scholia
319. Kim H, Huang W, Jiang X, Pennicooke B, Park PJ, Johnson MD.; ''Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship.''; PubMed Europe PMC Scholia
320. Brezski RJ, Monroe JG.; ''B-cell receptor.''; PubMed Europe PMC Scholia
321. Lang V, Aillet F, Da Silva-Ferrada E, Xolalpa W, Zabaleta L, Rivas C, Rodriguez MS.; ''Analysis of PTEN ubiquitylation and SUMOylation using molecular traps.''; PubMed Europe PMC Scholia
322. Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, Hegg JW, Bandhakavi S, Griffin TJ, Kim DH.; ''PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling.''; PubMed Europe PMC Scholia
323. Rönnstrand L.; ''Signal transduction via the stem cell factor receptor/c-Kit.''; PubMed Europe PMC Scholia
324. Meier R, Alessi DR, Cron P, Andjelković M, Hemmings BA.; ''Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta.''; PubMed Europe PMC Scholia
325. Eswarakumar VP, Lax I, Schlessinger J.; ''Cellular signaling by fibroblast growth factor receptors.''; PubMed Europe PMC Scholia
326. Maehama T, Dixon JE.; ''The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.''; PubMed Europe PMC Scholia
327. Kaushansky A, Gordus A, Budnik BA, Lane WS, Rush J, MacBeath G.; ''System-wide investigation of ErbB4 reveals 19 sites of Tyr phosphorylation that are unusually selective in their recruitment properties.''; PubMed Europe PMC Scholia
328. Zhang H.; ''Life without kinase: cyclin E promotes DNA replication licensing and beyond.''; PubMed Europe PMC Scholia
329. Yamanashi Y, Kakiuchi T, Mizuguchi J, Yamamoto T, Toyoshima K.; ''Association of B cell antigen receptor with protein tyrosine kinase Lyn.''; PubMed Europe PMC Scholia
330. Acuto O, Michel F.; ''CD28-mediated co-stimulation: a quantitative support for TCR signalling.''; PubMed Europe PMC Scholia
331. Naldini L, Vigna E, Narsimhan RP, Gaudino G, Zarnegar R, Michalopoulos GK, Comoglio PM.; ''Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET.''; PubMed Europe PMC Scholia
332. Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, Huang CH, Kinzler KW, Vogelstein B, Amzel LM.; ''A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane.''; PubMed Europe PMC Scholia
333. Di Paolo G, Pellegrini L, Letinic K, Cestra G, Zoncu R, Voronov S, Chang S, Guo J, Wenk MR, De Camilli P.; ''Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin.''; PubMed Europe PMC Scholia
334. Hou XJ, Ni KM, Yang JM, Li XM.; ''Neuregulin 1/ErbB4 enhances synchronized oscillations of prefrontal cortex neurons via inhibitory synapses.''; PubMed Europe PMC Scholia
335. Ornitz DM, Marie PJ.; ''FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease.''; PubMed Europe PMC Scholia
336. Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMed Europe PMC Scholia
337. Besser D, Bardelli A, Didichenko S, Thelen M, Comoglio PM, Ponzetto C, Nagamine Y.; ''Regulation of the urokinase-type plasminogen activator gene by the oncogene Tpr-Met involves GRB2.''; PubMed Europe PMC Scholia
338. Maina F, Hilton MC, Ponzetto C, Davies AM, Klein R.; ''Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons.''; PubMed Europe PMC Scholia
339. Connell-Crowley L, Harper JW, Goodrich DW.; ''Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation.''; PubMed Europe PMC Scholia
340. Hodakoski C, Hopkins BD, Barrows D, Mense SM, Keniry M, Anderson KE, Kern PA, Hawkins PT, Stephens LR, Parsons R.; ''Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis.''; PubMed Europe PMC Scholia
341. Kovacina KS, Park GY, Bae SS, Guzzetta AW, Schaefer E, Birnbaum MJ, Roth RA.; ''Identification of a proline-rich Akt substrate as a 14-3-3 binding partner.''; PubMed Europe PMC Scholia
342. Pelicci G, Giordano S, Zhen Z, Salcini AE, Lanfrancone L, Bardelli A, Panayotou G, Waterfield MD, Ponzetto C, Pelicci PG.; ''The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein.''; PubMed Europe PMC Scholia
343. Lessmann V, Gottmann K, Malcangio M.; ''Neurotrophin secretion: current facts and future prospects.''; PubMed Europe PMC Scholia
344. Minichiello L.; ''TrkB signalling pathways in LTP and learning.''; PubMed Europe PMC Scholia
345. Alegre ML, Frauwirth KA, Thompson CB.; ''T-cell regulation by CD28 and CTLA-4.''; PubMed Europe PMC Scholia
346. Hazan R, Margolis B, Dombalagian M, Ullrich A, Zilberstein A, Schlessinger J.; ''Identification of autophosphorylation sites of HER2/neu.''; PubMed Europe PMC Scholia
347. Geng F, Zhang J, Wu JL, Zou WJ, Liang ZP, Bi LL, Liu JH, Kong Y, Huang CQ, Li XW, Yang JM, Gao TM.; ''Neuregulin 1-ErbB4 signaling in the bed nucleus of the stria terminalis regulates anxiety-like behavior.''; PubMed Europe PMC Scholia
348. Tzahar E, Levkowitz G, Karunagaran D, Yi L, Peles E, Lavi S, Chang D, Liu N, Yayon A, Wen D.; ''ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms.''; PubMed Europe PMC Scholia
349. Collaud S, Tischler V, Atanassoff A, Wiedl T, Komminoth P, Oehlschlegel C, Weder W, Soltermann A.; ''Lung neuroendocrine tumors: correlation of ubiquitinylation and sumoylation with nucleo-cytosolic partitioning of PTEN.''; PubMed Europe PMC Scholia
350. Williams EJ, Furness J, Walsh FS, Doherty P.; ''Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin.''; PubMed Europe PMC Scholia
351. Cheng Q, Cross B, Li B, Chen L, Li Z, Chen J.; ''Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage.''; PubMed Europe PMC Scholia
352. Sun Y, Ikrar T, Davis MF, Gong N, Zheng X, Luo ZD, Lai C, Mei L, Holmes TC, Gandhi SP, Xu X.; ''Neuregulin-1/ErbB4 Signaling Regulates Visual Cortical Plasticity.''; PubMed Europe PMC Scholia
353. Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMed Europe PMC Scholia
354. Zhang CL, Zou Y, Yu RT, Gage FH, Evans RM.; ''Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1.''; PubMed Europe PMC Scholia
355. Tay Y, Rinn J, Pandolfi PP.; ''The multilayered complexity of ceRNA crosstalk and competition.''; PubMed Europe PMC Scholia
356. Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R, Kahr H, Madl J, Gruber H, Groschner K, Romanin C.; ''Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation.''; PubMed Europe PMC Scholia
357. Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMed Europe PMC Scholia
358. Li Z, Mei Y, Liu X, Zhou M.; ''Neuregulin-1 only induces trans-phosphorylation between ErbB receptor heterodimer partners.''; PubMed Europe PMC Scholia
359. Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH.; ''Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN.''; PubMed Europe PMC Scholia
360. Clarke JH, Wang M, Irvine RF.; ''Localization, regulation and function of type II phosphatidylinositol 5-phosphate 4-kinases.''; PubMed Europe PMC Scholia
361. Carraway KL, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, Lai C.; ''Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases.''; PubMed Europe PMC Scholia
362. Sakkab D, Lewitzky M, Posern G, Schaeper U, Sachs M, Birchmeier W, Feller SM.; ''Signaling of hepatocyte growth factor/scatter factor (HGF) to the small GTPase Rap1 via the large docking protein Gab1 and the adapter protein CRKL.''; PubMed Europe PMC Scholia
363. Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM.; ''A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family.''; PubMed Europe PMC Scholia
364. Ichim G, Genevois AL, Ménard M, Yu LY, Coelho-Aguiar JM, Llambi F, Jarrosson-Wuilleme L, Lefebvre J, Tulasne D, Dupin E, Le Douarin N, Arumäe U, Tauszig-Delamasure S, Mehlen P.; ''The dependence receptor TrkC triggers mitochondria-dependent apoptosis upon Cobra-1 recruitment.''; PubMed Europe PMC Scholia
365. Kirchhofer D, Yao X, Peek M, Eigenbrot C, Lipari MT, Billeci KL, Maun HR, Moran P, Santell L, Wiesmann C, Lazarus RA.; ''Structural and functional basis of the serine protease-like hepatocyte growth factor beta-chain in Met binding and signaling.''; PubMed Europe PMC Scholia
366. Harwood NE, Batista FD.; ''Early events in B cell activation.''; PubMed Europe PMC Scholia
367. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK.; ''The lipid phosphatase activity of PTEN is critical for its tumor supressor function.''; PubMed Europe PMC Scholia
368. Roskoski R.; ''ERK1/2 MAP kinases: structure, function, and regulation.''; PubMed Europe PMC Scholia
369. Pekarsky Y, Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y, Bichi R, Letofsky J, Croce CM.; ''Akt phosphorylates and regulates the orphan nuclear receptor Nur77.''; PubMed Europe PMC Scholia
370. Muraoka-Cook RS, Sandahl M, Hunter D, Miraglia L, Earp HS.; ''Prolactin and ErbB4/HER4 signaling interact via Janus kinase 2 to induce mammary epithelial cell gene expression differentiation.''; PubMed Europe PMC Scholia
371. Naresh A, Long W, Vidal GA, Wimley WC, Marrero L, Sartor CI, Tovey S, Cooke TG, Bartlett JM, Jones FE.; ''The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells.''; PubMed Europe PMC Scholia
372. Gual P, Giordano S, Williams TA, Rocchi S, Van Obberghen E, Comoglio PM.; ''Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis.''; PubMed Europe PMC Scholia
373. Shen K, Novak RF.; ''DDT stimulates c-erbB2, c-met, and STATS tyrosine phosphorylation, Grb2-Sos association, MAPK phosphorylation, and proliferation of human breast epithelial cells.''; PubMed Europe PMC Scholia
374. Palamidessi A, Frittoli E, Garré M, Faretta M, Mione M, Testa I, Diaspro A, Lanzetti L, Scita G, Di Fiore PP.; ''Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration.''; PubMed Europe PMC Scholia
375. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, Maira M, Garcia-Echeverria C, Parra JL, Arribas J, Baselga J.; ''NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations.''; PubMed Europe PMC Scholia
376. Mayo LD, Donner DB.; ''A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus.''; PubMed Europe PMC Scholia
377. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
ADP	Metabolite	CHEBI:16761 (ChEBI)
AKT inhibitors:AKT	Complex	REACT_148070 (Reactome)
AKT inhibitors	Metabolite	REACT_148563 (Reactome)
AKT/AKT1 E17K mutant	Protein	REACT_147936 (Reactome)
AKT1 E17K mutant:PIP2	Complex	REACT_148412 (Reactome)
AKT1 E17K mutant [plasma membrane]	Protein	P31749 (Uniprot-TrEMBL)
AKT1 E17K mutant	Protein	P31749 (Uniprot-TrEMBL)
AKT1S1	Protein	Q96B36 (Uniprot-TrEMBL)
AKT:PIP3:THEM4/TRIB3	Complex	REACT_12823 (Reactome)
AKT:PIP3	Complex	REACT_147984 (Reactome)
AKT	Protein	REACT_12946 (Reactome)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Activator:PI3K/PI3K mutants	Complex	REACT_148475 (Reactome)
Activator:PI3K	Complex	REACT_148170 (Reactome)
Active AKT	Protein	REACT_13116 (Reactome)
Active AKT	Protein	REACT_13319 (Reactome)
BAD	Protein	Q92934 (Uniprot-TrEMBL)
Betacellulin [extracellular region]	Protein	P35070 (Uniprot-TrEMBL)
CASP9(1-416)	Protein	P55211 (Uniprot-TrEMBL)	any remaining instances associated here should be reassociated with the complex Cleaved Caspase-9
CD80 [plasma membrane]	Protein	P33681 (Uniprot-TrEMBL)
CD86 [plasma membrane]	Protein	P42081 (Uniprot-TrEMBL)
CDKN1A/B	Protein	REACT_13380 (Reactome)
CHUK	Protein	O15111 (Uniprot-TrEMBL)
CREB1	Protein	P16220 (Uniprot-TrEMBL)
EGF(971-1023) [extracellular region]	Protein	P01133 (Uniprot-TrEMBL)
EIF2C1 [cytosol]	Protein	Q9UL18 (Uniprot-TrEMBL)
EIF2C2 [cytosol]	Protein	Q9UKV8 (Uniprot-TrEMBL)
EIF2C3 [cytosol]	Protein	Q9H9G7 (Uniprot-TrEMBL)
EIF2C4 [cytosol]	Protein	Q9HCK5 (Uniprot-TrEMBL)
Epiregulin [extracellular region]	Protein	O14944 (Uniprot-TrEMBL)
FGF1 [extracellular region]	Protein	P05230 (Uniprot-TrEMBL)
FGF10 [extracellular region]	Protein	O15520 (Uniprot-TrEMBL)
FGF16 [extracellular region]	Protein	O43320 (Uniprot-TrEMBL)
FGF17-1 [extracellular region]	Protein	O60258-1 (Uniprot-TrEMBL)
FGF18 [extracellular region]	Protein	O76093 (Uniprot-TrEMBL)
FGF19 [extracellular region]	Protein	O95750 (Uniprot-TrEMBL)
FGF2(10-155) [extracellular region]	Protein	P09038 (Uniprot-TrEMBL)
FGF20 [extracellular region]	Protein	Q9NP95 (Uniprot-TrEMBL)
FGF22 [extracellular region]	Protein	Q9HCT0 (Uniprot-TrEMBL)
FGF23(25-251) [extracellular region]	Protein	Q9GZV9 (Uniprot-TrEMBL)
FGF3 [extracellular region]	Protein	P11487 (Uniprot-TrEMBL)
FGF4 [extracellular region]	Protein	P08620 (Uniprot-TrEMBL)
FGF5-1 [extracellular region]	Protein	P12034-1 (Uniprot-TrEMBL)
FGF6 [extracellular region]	Protein	P10767 (Uniprot-TrEMBL)
FGF7 [extracellular region]	Protein	P21781 (Uniprot-TrEMBL)
FGF8-1 [extracellular region]	Protein	P55075-1 (Uniprot-TrEMBL)
FGF9 [extracellular region]	Protein	P31371 (Uniprot-TrEMBL)
FYN(2-537) [cytosol]	Protein	P06241 (Uniprot-TrEMBL)
Forkhead box transcription factor	Protein	REACT_13013 (Reactome)
GAB1 [cytosol]	Protein	Q13480 (Uniprot-TrEMBL)
GRB2-1 [cytosol]	Protein	P62993-1 (Uniprot-TrEMBL)
GRB2-1 [plasma membrane]	Protein	P62993-1 (Uniprot-TrEMBL)
GSK3	Protein	REACT_13050 (Reactome)
H2O	Metabolite	CHEBI:15377 (ChEBI)
HBEGF(63-148) [extracellular region]	Protein	Q99075 (Uniprot-TrEMBL)
Heparan Sulphate [extracellular region]	Metabolite	CHEBI:28815 (ChEBI)
Intrinsic Pathway for Apoptosis	Pathway	WP1841 (WikiPathways)	The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows: 1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption. 2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.
KITLG-1(26-190) [extracellular region]	Protein	P21583-1 (Uniprot-TrEMBL)
KL-1 [plasma membrane]	Protein	Q9UEF7-1 (Uniprot-TrEMBL)
KL-2 [extracellular region]	Protein	Q9UEF7-2 (Uniprot-TrEMBL)
KLB [plasma membrane]	Protein	Q86Z14 (Uniprot-TrEMBL)
LCK [cytosol]	Protein	P06239 (Uniprot-TrEMBL)
MAPKAP1 [cytosol]	Protein	Q9BPZ7 (Uniprot-TrEMBL)
MDM2	Protein	Q00987 (Uniprot-TrEMBL)
MK2206 [cytosol]	Metabolite	CHEBI:716367 (ChEBI)
MLST8 [cytosol]	Protein	Q9BVC4 (Uniprot-TrEMBL)
MOV10 [cytosol]	Protein	Q9HCE1 (Uniprot-TrEMBL)
MTOR [cytosol]	Protein	P42345 (Uniprot-TrEMBL)
Mg2+ [cytosol]	Metabolite	CHEBI:18420 (ChEBI)
Mn2+ [cytosol]	Metabolite	CHEBI:18291 (ChEBI)
NR4A1	Protein	P22736 (Uniprot-TrEMBL)
PDGFA-1 [extracellular region]	Protein	P04085-1 (Uniprot-TrEMBL)
PDGFA-2 [extracellular region]	Protein	P04085-2 (Uniprot-TrEMBL)
PDGFB [extracellular region]	Protein	P01127 (Uniprot-TrEMBL)
PDGFB(82-241) [extracellular region]	Protein	P01127 (Uniprot-TrEMBL)
PDPK1 [plasma membrane]	Protein	O15530 (Uniprot-TrEMBL)
PDPK1:PIP2	Complex	REACT_148508 (Reactome)
PDPK1:PIP3	Complex	REACT_148385 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2	Complex	REACT_148312 (Reactome)
PDPK1	Protein	O15530 (Uniprot-TrEMBL)
PHLPP (Mn2+ cofactor)	Complex	REACT_13329 (Reactome)
PHLPP1 [cytosol]	Protein	O60346 (Uniprot-TrEMBL)
PHLPP2 [cytosol]	Protein	Q6ZVD8 (Uniprot-TrEMBL)
PI(3,4,5)P3 [plasma membrane]	Metabolite	CHEBI:16618 (ChEBI)
PI(3,4,5)P3	Metabolite	CHEBI:16618 (ChEBI)
PI(4,5)P2 [plasma membrane]	Metabolite	CHEBI:18348 (ChEBI)
PI(4,5)P2	Metabolite	CHEBI:18348 (ChEBI)
PI3K Inhibitors:PI3K	Complex	REACT_148204 (Reactome)
PI3K inhibitors	Metabolite	REACT_148311 (Reactome)	PI3K inhibitors bind the catalytic subunit of PIK3CA, blocking its phosphoinositide kinase activity.
PI3K mutants	Complex	REACT_148388 (Reactome)
PIK3CA [cytosol]	Protein	P42336 (Uniprot-TrEMBL)
PIK3CB [cytosol]	Protein	P42338 (Uniprot-TrEMBL)
PIK3CD [plasma membrane]	Protein	O00329 (Uniprot-TrEMBL)
PIK3R1 G376R mutant [plasma membrane]	Protein	P27986 (Uniprot-TrEMBL)	The substitution of glycine residue with arginine at position 376 in the nSH2 domain of PIK3R1 relieves the inhibitory effect on the PI3K catalytic subunit, PIK3CA, resulting in constitutive activity of PI3K complex that contains PIK3R1 G376R mutant (Sun et al. 2010).
PIK3R1 [cytosol]	Protein	P27986 (Uniprot-TrEMBL)
PIK3R1 [plasma membrane]	Protein	P27986 (Uniprot-TrEMBL)
PIK3R2 [cytosol]	Protein	O00459 (Uniprot-TrEMBL)
PTEN Mutants	Protein	REACT_148130 (Reactome)
PTEN [cytosol]	Protein	P60484 (Uniprot-TrEMBL)
PTEN mRNA [cytosol]	Protein	ENST00000371953 (ENSEMBL)
PTEN mRNA:miR-26A RISC	Complex	REACT_147972 (Reactome)
PTEN mRNA	Rna	ENST00000371953 (ENSEMBL)
PTEN:Mg2+	Complex	REACT_12877 (Reactome)
Phospho-Forkhead box transcription factor	Protein	REACT_13209 (Reactome)
Phosphorylated Fibroblast growth factor receptor 2b short [plasma membrane]	Protein	P21802-18 (Uniprot-TrEMBL)
Pi	Metabolite	CHEBI:18367 (ChEBI)
RICTOR [cytosol]	Protein	Q6R327 (Uniprot-TrEMBL)
RPS6KB2	Protein	Q9UBS0 (Uniprot-TrEMBL)
THEM4 [plasma membrane]	Protein	Q5T1C6 (Uniprot-TrEMBL)
THEM4/TRIB3	Protein	REACT_148496 (Reactome)
TNRC6A [cytosol]	Protein	Q8NDV7 (Uniprot-TrEMBL)
TNRC6B [cytosol]	Protein	Q9UPQ9 (Uniprot-TrEMBL)
TNRC6C [cytosol]	Protein	Q9HCJ0 (Uniprot-TrEMBL)
TORC2 complex	Complex	REACT_13222 (Reactome)
TRIB3 [plasma membrane]	Protein	Q96RU7 (Uniprot-TrEMBL)
TSC2	Protein	P49815 (Uniprot-TrEMBL)
Triciribine [cytosol]	Metabolite	CHEBI:65310 (ChEBI)
VAV1 [plasma membrane]	Protein	P15498 (Uniprot-TrEMBL)
miR-26A RISC	Complex	REACT_148347 (Reactome)
miR-26A1 [cytosol]	Protein	MI0000083 (miRBase)
miR-26A2 [cytosol]	Protein	MI0000750 (miRBase)
p-11Y-PDGFRA [plasma membrane]	Protein	P16234 (Uniprot-TrEMBL)
p-12Y-PDGFRB [plasma membrane]	Protein	P09619 (Uniprot-TrEMBL)
p-5Y-FGFR4 [plasma membrane]	Protein	P22455 (Uniprot-TrEMBL)
p-6Y-CD19 [plasma membrane]	Protein	P15391 (Uniprot-TrEMBL)
p-6Y-EGFR [plasma membrane]	Protein	P00533 (Uniprot-TrEMBL)
p-6Y-FRS2 [plasma membrane]	Protein	Q8WU20 (Uniprot-TrEMBL)
p-7Y-KIT [plasma membrane]	Protein	P10721 (Uniprot-TrEMBL)
p-8Y-FGFR2-3 [plasma membrane]	Protein	P21802-3 (Uniprot-TrEMBL)
p-8Y-FGFR2-5 [plasma membrane]	Protein	P21802-5 (Uniprot-TrEMBL)
p-8xY-FGFR2c long [plasma membrane]	Protein	P21802-1 (Uniprot-TrEMBL)
p-S-AKT:PDPK1:PIP3	Complex	REACT_148335 (Reactome)
p-S-AKT:PIP3	Complex	REACT_148552 (Reactome)
p-S133-CREB1	Protein	P16220 (Uniprot-TrEMBL)
p-S15,S356-RPS6KB2	Protein	Q9UBS0 (Uniprot-TrEMBL)
p-S166,S188-MDM2	Protein	Q00987 (Uniprot-TrEMBL)
p-S183,T246-AKT1S1	Protein	Q96B36 (Uniprot-TrEMBL)
p-S196-CASP9(1-416)	Protein	P55211 (Uniprot-TrEMBL)	any remaining instances associated here should be reassociated with the complex Cleaved Caspase-9
p-S351-NR4A1	Protein	P22736 (Uniprot-TrEMBL)
p-S473-AKT1 E17K mutant [plasma membrane]	Protein	P31749 (Uniprot-TrEMBL)
p-S473-AKT1 E17K mutant:PIP2	Complex	REACT_148525 (Reactome)
p-S9/21-GSK3	Protein	REACT_13164 (Reactome)
p-S939,T1462-TSC2	Protein	P49815 (Uniprot-TrEMBL)
p-S99-BAD	Protein	Q92934 (Uniprot-TrEMBL)
p-T-AKT	Protein	REACT_12669 (Reactome)
p-T-CDKN1A/B	Protein	REACT_12999 (Reactome)
p-T23-CHUK	Protein	O15111 (Uniprot-TrEMBL)
p-T308,S473-AKT1 E17K mutant	Protein	P31749 (Uniprot-TrEMBL)
p-Y-IRS1 [plasma membrane]	Protein	P35568 (Uniprot-TrEMBL)
p-Y-IRS2 [plasma membrane]	Protein	Q9Y4H2 (Uniprot-TrEMBL)
p-Y1046,Y1178,Y1232-ERBB4 JM-B CYT-1 isoform [plasma membrane]	Protein	Q15303-2 (Uniprot-TrEMBL)
p-Y1056,Y1188,Y1242-ERBB4 JM-A CYT-1 isoform [plasma membrane]	Protein	Q15303-1 (Uniprot-TrEMBL)
p-Y191-CD28 [plasma membrane]	Protein	P10747 (Uniprot-TrEMBL)
p-Y546,Y584-PTPN11 [cytosol]	Protein	Q06124 (Uniprot-TrEMBL)
p-Y63,Y79,Y110-TRAT1 [plasma membrane]	Protein	Q6PIZ9 (Uniprot-TrEMBL)
perifosine [cytosol]	Metabolite	CHEBI:428891 (ChEBI)
phosphorylated FGFR1c [plasma membrane]	Protein	P11362-1 (Uniprot-TrEMBL)
phosphorylated FGFR3b [plasma membrane]	Protein	P22607-2 (Uniprot-TrEMBL)
phosphorylated FGFR3c [plasma membrane]	Protein	P22607-1 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	ADP	Arrow	REACT_12383 (Reactome)
	ADP	Arrow	REACT_12391 (Reactome)
	ADP	Arrow	REACT_12395 (Reactome)
	ADP	Arrow	REACT_12420 (Reactome)
	ADP	Arrow	REACT_12461 (Reactome)
	ADP	Arrow	REACT_12485 (Reactome)
	ADP	Arrow	REACT_12532 (Reactome)
	ADP	Arrow	REACT_12537 (Reactome)
	ADP	Arrow	REACT_12549 (Reactome)
	ADP	Arrow	REACT_12565 (Reactome)
	ADP	Arrow	REACT_12572 (Reactome)
	ADP	Arrow	REACT_12584 (Reactome)
	ADP	Arrow	REACT_12597 (Reactome)
	ADP	Arrow	REACT_12614 (Reactome)
	ADP	Arrow	REACT_147781 (Reactome)
	ADP	Arrow	REACT_147846 (Reactome)
	ADP	Arrow	REACT_147858 (Reactome)
	ADP	Arrow	REACT_147862 (Reactome)
	AKT inhibitors:AKT	Arrow	REACT_147895 (Reactome)
AKT inhibitors			REACT_147895 (Reactome)
AKT/AKT1 E17K mutant			REACT_147895 (Reactome)
	AKT1 E17K mutant:PIP2	Arrow	REACT_147896 (Reactome)
AKT1 E17K mutant:PIP2			REACT_147858 (Reactome)
AKT1 E17K mutant			REACT_147896 (Reactome)
AKT1S1			REACT_12383 (Reactome)
	AKT:PIP3:THEM4/TRIB3	Arrow	REACT_12567 (Reactome)
AKT:PIP3:THEM4/TRIB3		TBar	REACT_12391 (Reactome)
	AKT:PIP3	Arrow	REACT_147886 (Reactome)
AKT:PIP3			REACT_12391 (Reactome)
AKT:PIP3			REACT_12567 (Reactome)
AKT			REACT_147886 (Reactome)
ATP			REACT_12383 (Reactome)
ATP			REACT_12391 (Reactome)
ATP			REACT_12395 (Reactome)
ATP			REACT_12420 (Reactome)
ATP			REACT_12461 (Reactome)
ATP			REACT_12485 (Reactome)
ATP			REACT_12532 (Reactome)
ATP			REACT_12537 (Reactome)
ATP			REACT_12549 (Reactome)
ATP			REACT_12565 (Reactome)
ATP			REACT_12572 (Reactome)
ATP			REACT_12584 (Reactome)
ATP			REACT_12597 (Reactome)
ATP			REACT_12614 (Reactome)
ATP			REACT_147781 (Reactome)
ATP			REACT_147846 (Reactome)
ATP			REACT_147858 (Reactome)
ATP			REACT_147862 (Reactome)
Activator:PI3K/PI3K mutants			REACT_147854 (Reactome)
Activator:PI3K		mim-catalysis	REACT_147781 (Reactome)
	Active AKT	Arrow	REACT_12558 (Reactome)
	Active AKT	Arrow	REACT_12584 (Reactome)
Active AKT			REACT_12403 (Reactome)
Active AKT			REACT_12558 (Reactome)
Active AKT		mim-catalysis	REACT_12383 (Reactome)
Active AKT		mim-catalysis	REACT_12395 (Reactome)
Active AKT		mim-catalysis	REACT_12420 (Reactome)
Active AKT		mim-catalysis	REACT_12461 (Reactome)
Active AKT		mim-catalysis	REACT_12485 (Reactome)
Active AKT		mim-catalysis	REACT_12532 (Reactome)
Active AKT		mim-catalysis	REACT_12537 (Reactome)
Active AKT		mim-catalysis	REACT_12549 (Reactome)
Active AKT		mim-catalysis	REACT_12565 (Reactome)
Active AKT		mim-catalysis	REACT_12572 (Reactome)
Active AKT		mim-catalysis	REACT_12597 (Reactome)
Active AKT		mim-catalysis	REACT_12614 (Reactome)
BAD			REACT_12565 (Reactome)
CASP9(1-416)			REACT_12395 (Reactome)
CDKN1A/B			REACT_12420 (Reactome)
CHUK			REACT_12461 (Reactome)
CREB1			REACT_12597 (Reactome)
Forkhead box transcription factor			REACT_12572 (Reactome)
GSK3			REACT_12549 (Reactome)
H2O			REACT_12403 (Reactome)
H2O			REACT_12542 (Reactome)
H2O			REACT_147756 (Reactome)
MDM2			REACT_12537 (Reactome)
NR4A1			REACT_12614 (Reactome)
	PDPK1:PIP2	Arrow	REACT_147701 (Reactome)
	PDPK1:PIP2	Arrow	REACT_147862 (Reactome)
PDPK1:PIP2			REACT_147790 (Reactome)
	PDPK1:PIP3	Arrow	REACT_12584 (Reactome)
	PDPK1:PIP3	Arrow	REACT_147873 (Reactome)
PDPK1:PIP3			REACT_147711 (Reactome)
	PDPK1:p-S473-AKT1 E17K mutant:PIP2	Arrow	REACT_147790 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2			REACT_147862 (Reactome)
PDPK1:p-S473-AKT1 E17K mutant:PIP2		mim-catalysis	REACT_147862 (Reactome)
PDPK1			REACT_147701 (Reactome)
PDPK1			REACT_147873 (Reactome)
PHLPP (Mn2+ cofactor)		mim-catalysis	REACT_12403 (Reactome)
	PI(3,4,5)P3	Arrow	REACT_147781 (Reactome)
	PI(3,4,5)P3	Arrow	REACT_147846 (Reactome)
PI(3,4,5)P3			REACT_12542 (Reactome)
PI(3,4,5)P3			REACT_147756 (Reactome)
PI(3,4,5)P3			REACT_147873 (Reactome)
PI(3,4,5)P3			REACT_147886 (Reactome)
	PI(4,5)P2	Arrow	REACT_12542 (Reactome)
PI(4,5)P2			REACT_147701 (Reactome)
PI(4,5)P2			REACT_147781 (Reactome)
PI(4,5)P2			REACT_147846 (Reactome)
PI(4,5)P2			REACT_147896 (Reactome)
	PI3K Inhibitors:PI3K	Arrow	REACT_147854 (Reactome)
PI3K inhibitors			REACT_147854 (Reactome)
PI3K mutants		mim-catalysis	REACT_147846 (Reactome)
PTEN Mutants		mim-catalysis	REACT_147756 (Reactome)
	PTEN mRNA:miR-26A RISC	Arrow	REACT_147761 (Reactome)
PTEN mRNA:miR-26A RISC		TBar	REACT_147819 (Reactome)
PTEN mRNA			REACT_147761 (Reactome)
PTEN mRNA			REACT_147819 (Reactome)
	PTEN:Mg2+	Arrow	REACT_147819 (Reactome)
PTEN:Mg2+		mim-catalysis	REACT_12542 (Reactome)
	Phospho-Forkhead box transcription factor	Arrow	REACT_12572 (Reactome)
	Pi	Arrow	REACT_12403 (Reactome)
	Pi	Arrow	REACT_12542 (Reactome)
			REACT_12383 (Reactome)	PRAS40 (proline-rich Akt/PKB substrate 40 kDa) is a substrate of AKT, the phosphorylation of which leads to the binding of this protein to 14-3-3. PRAS40 binds to mTOR complexes, mediating AKT signals to mTOR. Interaction of PRAS40 with the mTOR kinase domain is induced under conditions that inhibit mTOR signalling, such as growth factor deprivation. Binding of PRAS40 inhibits mTOR. PRAS40 phosphorylation by AKT and association with the cytosolic anchor protein 14-3-3, lead to mTOR stimulation (Vander Haar E, et al, 2007). Although it was originally identified in the context of insulin signalling, it was later shown that PRAS40 may also play a role in nerve growth factor-mediated neuroprotection (Saito A, et al, 2004).
			REACT_12391 (Reactome)	Under conditions of growth and mitogen stimulation S473 phosphorylation of AKT is carried out by mTOR (mammalian Target of Rapamycin). This kinase is found in two structurally and functionally distinct protein complexes, named TOR complex 1 (TORC1) and TOR complex 2 (TORC2). It is TORC2 complex, which is composed of mTOR, RICTOR, SIN1 (also named MAPKAP1) and LST8, that phosphorylates AKT at S473 (Sarbassov et al., 2005). This complex also regulates actin cytoskeletal reorganization (Jacinto et al., 2004; Sarbassov et al., 2004). TORC1, on the other hand, is a major regulator of ribosomal biogenesis and protein synthesis (Hay and Sonenberg, 2004). TORC1 regulates these processes largely by the phosphorylation/inactivation of the repressors of mRNA translation 4E binding proteins (4E BPs) and by the phosphorylation/activation of ribosomal S6 kinase (S6K1). TORC1 is also the principal regulator of autophagy. In other physiological conditions, other kinases may be responsible for AKT S473 phosphorylation. Phosphorylation of AKT on S473 by TORC2 complex is a prerequisite for AKT phosphorylation on T308 by PDPK1 (Scheid et al. 2002, Sarabassov et al. 2005).
			REACT_12395 (Reactome)	AKT can phosphorylate the apoptotic protease caspase-9, inhibiting it.
			REACT_12403 (Reactome)	The PH domain leucine-rich repeat-containing protein phosphatases, PHLPP1 (Gao et al. 2005) and PHLPP2 (Brognard et al. 2007) can specifically dephosphorylate the serine residue and inactivate AKT.
			REACT_12420 (Reactome)	Phosphorylation of p27Kip1 at T157 and of p21Cip1 at T145 by AKT leads to their retention in the cytoplasm, segregating these cyclin-dependent kinase (CDK) inhibitors from cyclin-CDK complexes.
			REACT_12461 (Reactome)	AKT mediates IKKalpha (Inhibitor of nuclear factor kappa B kinase subunit alpha) phosphorylation at threonine 23, which is required for NF-kB activation. NF-kB promoted gene transcription enhances neuronal survival.
			REACT_12485 (Reactome)	Ribosomal protein S6 kinase beta-2 (RSK) activation is a highly conserved mitogenic response, and the activities of RSK are stimulated by multiple serine/threonine phosphorylations by different upstream kinases, one of which is AKT.
			REACT_12532 (Reactome)	AKT phosphorylates and inhibits TSC2 (tuberin), a suppressor of the TOR kinase pathway, which senses nutrient levels in the environment. TSC2 forms a TSC1-TSC2 protein complex that is a GAP (GTPase activating protein) for the RHEB G-protein. RHEB, in turn, activates the TOR kinase. Thus, an active AKT1 activates the TOR kinase, both of which are positive signals for cell growth (an increase in cell mass) and division. The TOR kinase regulates two major processes: translation of selected mRNAs in the cell and autophagy. In the presence of high nutrient levels TOR is active and phosphorylates the 4EBP protein releasing the eukaryotic initiation factor 4E (eIF4E), which is essential for cap-dependent initiation of translation and promoting growth of the cell (PMID: 15314020). TOR also phosphorylates the S6 kinase, which is implicated in ribosome biogenesis as well as in the modification of the S6 ribosomal protein. AKT can also activate mTOR by another mechanism, involving phosphorylation of PRAS40, an inhibitor of mTOR activity.
			REACT_12537 (Reactome)	AKT phosphorylates MDM2 on two serine residues, at positions 166 and 188 (Feng et al. 2004, Milne et al. 2004). AKT-mediated phosphorylation of ubiquitin-protein ligase E3 MDM2 promotes nuclear localization and inhibits interaction between MDM2 and p19ARF, thereby decreasing p53 stability. This leads to a decreased expression of p53 target genes, such as BAX, that promote apoptosis (Zhou et al. 2001).
			REACT_12542 (Reactome)	The PI3K network is negatively regulated by phospholipid phosphatases that dephosphorylate PIP3, thus hampering AKT activation (Maehema et al. 1998). The tumour suppressor PTEN is the primary phospholipid phosphatase. The role of other phosphoinositide phosphatases (INPP5D, INPPL1, INPP5K, PTPRQ, INPP4B) in the negative regulation of PI3K/AKT signaling will be described in future editions of Reactome.
			REACT_12549 (Reactome)	GSK3 (glycogen synthase kinase-3) participates in the Wnt signaling pathway. It is implicated in the hormonal control of several regulatory proteins including glycogen synthase, and the transcription factors MYB and JUN. GSK3 phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. GSK3 is inhibited when phosphorylated by AKT1.
			REACT_12558 (Reactome)	AKT, phosphorylated at threonine (AKT1 308; AKT2 309; AKT3 305) and serine (AKT1 473; AKT2 474; AKT3 472) translocates to the nucleus, reaching a maximum after 15 min and returning to a basal level after 45 min of NGF stimulation. Control of the amount of nuclear AKT is achieved through the action of the phosphatase PP2A.
			REACT_12565 (Reactome)	Activated AKT phosphorylates the BCL-2 family member BAD at serine 99 (corresponds to serine residue S136 of mouse Bad), blocking the BAD-induced cell death (Datta et al. 1997, del Peso et al. 1997, Khor et al. 2004).
			REACT_12567 (Reactome)	The phosphorylation of membrane-recruited AKT at threonine and serine can be inhibited by direct binding of two different proteins, C-terminal modulator protein (THEM4 i.e. CTMP), which binds to the carboxy-terminal tail of AKT (Maira et al. 2001), or Tribbles homolog 3 (TRIB3), which binds to the catalytic domain of AKT (Du et al. 2003).
			REACT_12572 (Reactome)	Cell survival and growth are also promoted by AKT phosphorylation of Forkhead box (FOX) transcription factors, most notably FoxO1, FoxO3a and FoxO4. Once phosphorylated by AKT, these factors are removed from the nucleus, associate with 14-3-3 proteins, and are retained in the cytoplasm, thus producing a change in their transcriptional activity. For instance, unphosphorylated FoxO3a in the nucleus triggers apoptosis, most likely by inducing the expression of critical genes, such as the Fas ligand gene. In another example, AKT phosphorylation of FOXO4 prevents FOXO4-mediated upregulation of p27Kip1.
			REACT_12584 (Reactome)	Once AKT is localized at the plasma membrane, it is phosphorylated at two critical residues for its full activation. These residues are a threonine (T308 in AKT1) in the activation loop within the catalytic domain, and a serine (S473 in AKT1), in a hydrophobic motif (HM) within the carboxy terminal, non-catalytic region. PDPK1 (PDK1) is the activation loop kinase; this kinase can also directly phosphorylate p70S6K. The HM kinase, previously termed PDK2, has been identified as the mammalian TOR (Target Of Rapamycin; Sarbassov et al., 2005) but several other kinases are also able to phosphorylate AKT at S473. Phosphorylation of AKT at S473 by TORC2 complex is a prerequisite for PDPK1-mediated phosphorylation of AKT threonine T308 (Scheid et al. 2002, Sarabassov et al. 2005).
			REACT_12597 (Reactome)	AKT phosphorylates CREB (cAMP response element-binding protein) at serine 133 and activates gene expression via a CREB-dependent mechanism, thus promoting cell survival.
			REACT_12614 (Reactome)	AKT inhibits DNA binding of NUR77 and inhibits its pro-apoptotic function (PMID 11438550). However, the relevance of AKT for NUR77 phosphorylation has recently been questioned: according to recent work, NUR77 is phosphorylated by RSK (and MSK) rather than by AKT (PMID 16223362).
			REACT_147701 (Reactome)	PDPK1 (PDK1) possesses low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane, in the absence of PI3K activity (Currie et al. 1999).
			REACT_147711 (Reactome)	Once phosphorylated on serine residue S473, AKT bound to PIP3 forms a complex with PIP3-bound PDPK1 i.e. PDK1 (Scheid et al. 2002, Sarabassov et al. 2005)
			REACT_147756 (Reactome)	One of the functions of PTEN is to act as a phosphoinositide phosphatase that catalyzes dephosphorylation of PIP3 into PIP2. PTEN thus reduces the amount of available PIP3, counteracting PI3K activity and downregulating AKT signaling. PTEN is frequently targeted by loss of function mutations in cancer and in familial cancer syndromes known as PTHS (PTEN hamartoma tumor syndromes, a collection of diseases including Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Lhermitte-Duclos disease). Some PTEN loss-of-function variants are also found in autism spectrum disorder patients. For a recent review of PTEN involvement in cancer, please refer to Hollander et al. 2011. The majority of missense mutations that impair phosphoinositide phosphatase activity of PTEN cluster in exon 5 of PTEN gene and result in substitution of amino acid residues in the catalytic cleft of the phosphatase domain. Arginine at position 130 is the most frequently substituted PTEN residue in cancer. R130 of human PTEN is the last arginine residue in the conserved H-C-K/R-A-G-K-G-R sequence (corresponding to HCXXGXXR motif of protein tyrosine phosphatases) in the catalytic cleft of the PTEN phosphatase domain and is essential for catalysis (Barford et al. 1994, Lee et al. 1999). PTEN R130 substitution mutants show markedly decreased phosphoinositide phosphatase activity (Han et al. 2000, Koul et al. 2002) and are frequently found in endometrial carcinoma (Kong et al. 1997, Konopka et al. 2007). The cysteine residue at position 124 (C124) of human PTEN, in the conserved H-C-K/R-A-G-K-G-R sequence, 'attacks' the phosphate group of a substrate and forms a thio-phosphate intermediate during the dephosphorylation reaction (Guan and Dixon 1991, Barford et al. 1994, Lee et al. 1999). Therefore, substitution of this critical C124 abolishes PTEN phosphatase activity (Han et al. 2000, Koul et al. 2002). Substitution of histidine H123 in the conserved H-C-K/R-A-G-K-G-R sequence also impairs PTEN phosphatase activity (Lee et al. 1999). Missense mutations also target amino acid residues in the N-terminal phosphatase domain that are outside the catalytic cleft. Substitution of histidine at position 93 affects the conserved WPD loop of the phosphatase domain of PTEN, and PTEN H93 mutants show low phosphoinositide phosphatase activity (Lee et al. 1999). Serine residue S170 and histidine residue H173 participate in the formation of hydrogen bonds between the N-terminal phosphatase domain of PTEN and the C-terminal membrane-binding C2 domain (Lee et al. 1999). H173, and to a lesser extent S170, are targeted by missense mutations in cancer, and substitution mutants have impaired phosphoinositide phosphatase activity (Han et al. 2000). Missense mutations also occur in the C2 domain of PTEN. The C2 domain is implicated in membrane binding and localization of PTEN, but also in PTEN roles unrelated to its phosphoinositide phosphatase function (Raftopoulou et al. 2004). Since the roles of these C2 domain PTEN mutants in cancer have not been clarified, these variants will be annotated when more information becomes available. Besides missense mutations, nonsense mutations that result in PTEN protein truncation are also frequently found in cancer samples. The three residues most frequently targeted by nonsense mutations are R130, R233 and R335. While R130* mutation directly affects the phosphatase domain of PTEN, R233* and R335* affect the C2 domain. It is has not yet been elucidated whether R233* and R335* affect PTEN membrane localization or impair PTEN function in some other way. In cancer, PTEN is also frequently inactivated by genomic deletions and loss of heterozygosity (LOH) affecting chromosome band 10q23 or by epigenetic silencing (reviewed by Hollander et al. 2011).
			REACT_147761 (Reactome)	MIR26A microRNAs, miR-26A1 and miR-26A2, transcribed from genes on chromosome 3 and 12, respectively, bind PTEN mRNA (Huse et al. 2009). The MIR26A2 locus is frequently amplified in glioma tumors that retained one wild-type PTEN allele. The resulting miR-26A2 overexpression leads to downregulation of PTEN protein level. Overexpression of miR-26A2 was shown to enhance tumorigenesis and prevent loss of heterozigosity at the PTEN locus in a mouse PTEN +/- glioma model, based on a monoallelic PTEN loss (Huse et al. 2009, Kim et al. 2010).
			REACT_147781 (Reactome)	A number of different extracellular signals converge on PI3K activation. PI3K can be activated downstream of receptor tyrosine kinases (RTKs) such as FGFR (Ong et al. 2001, Eswarakumar et al. 2005), KIT (Chian et al. 2001, Ronnstrand 2004, Reber et al. 2006), PDGF (Coughlin et al. 1989, Fantl et al. 1992, Heldin et al. 1998), insulin receptor IGF1R (Hadari et al. 1992, Kooijman et al. 1995), and EGFR and its family members (Rodrigues et al. 2000, Jackson et al. 2004, Kainulainen et al. 2000, Junttila et al. 2009). Other proteins, such as CD28 (Pages et al. 1996, Koyasu 2003, Kane and Weiss, 2003) and TRAT1 (Bruyns et al. 1998, Koyasu 2003, Kolsch et al. 2006), can also trigger PI3K activity. In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011).
			REACT_147790 (Reactome)	A portion of PDPK1 (PDK1) is anchored to the plasma membrane in the absence of PI3K activity through PIP2 binding (Currie et al. 1999). This PIP2-bound PDPK1 is able to bind and phosphorylate PIP2-bound AKT E17K mutants (Carpten et al. 2007, Landgraf et al. 2008) phosphorylated on serine residue S473.
			REACT_147819 (Reactome)	PTEN protein synthesis is negatively regulated by microRNAs miR-26A1 and miR-26A2, which recruit the RISC complex to PTEN mRNA. Overexpression of miR-26A2, caused by genomic amplification of MIR26A2 locus on chromosome 12, is frequently observed in human brain glioma tumors possessing one wild-type PTEN allele, and is thought to contribute to tumor progression by repressing the remaining PTEN protein expression (Huse et al. 2009).
			REACT_147846 (Reactome)	Constitutively active PI3K complex produces PIP3 in the absence of growth stimuli, resulting in aberrant activation of downstream AKT signaling that positively regulates cell growth and survival. The PIK3CA gene, encoding the catalytic subunit of PI3K (p110alpha), is one of the most frequently mutated oncogenes in cancer. Hotspot mutations are found in the helical domain and kinase domain of PIK3CA, with the most frequent mutations being E545K substitution in the helical domain and H1047R substitution in the kinase domain. The oncogenic PIK3CA mutants annotated here preserve their ability to bind PIK3R1 (p85alpha) regulatory subunit, but are constitutively active either because the inhibitory interactions with PIK3R1 are relieved, or because the conformation of the catalytic domain is changed. Missense mutations that result in substitution of amino acids at positions 542, 545 or 546 of PI3K disrupt an inhibitory interaction between the helical domain of PIK3CA and the nSH2 domain of PIK3R1. The effect of substitution of glutamic acid residue at position 545 has been studied in detail in PIK3CA E545K mutant, where glutamic acid is replaced with lysine (Miled et al. 2007, Huang et al. 2007, Zhao et al. 2005). The gain-of-function has been experimentally confirmed for PIK3CA E545A mutant (Horn et al. 2008), while PIK3CA E545G, PIK3CA E545Q and PIK3CA E545V mutants are assumed to behave similarly. The structural and functional consequences of glutamic acid to lysine substitution at position 542, in PIK3CA E542K mutant, have been established (Miled et al. 2007, Horn et al. 2008) and are extrapolated to PIK3CA E542Q and PIK3CA E542V mutants. A less frequent substitution of glutamine residue at position 546 follows the same mechanism, as shown for PIK3CA Q546K mutant (Miled et al. 2007) and extrapolated to PIK3CA Q546E, PIK3CA Q546H, PIK3CA Q546L, PIK3CA Q546P and PIK3CA Q546R mutants. In the kinase domain of PIK3CA, substitution of histidine residue at position 1047 or methionine residue at position 1043, detected in PIK3CA H1047R, PIK3CA H1047L, PIK3CA H1047Y, PIK3CA M1043I, PIK3CA M1043T and PIK3CA M1043V mutants, is predicted to change the conformation of the activation loop (Huang et al. 2007) and was shown to confer constitutive activity, in the absence of growth factors, to PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants (Zhao et al. 2005, Horn et al. 2008). The catalytic activity of PIK3CA H1047R, PIK3CA H1047L and PIK3CA M1043I mutants may be further increased by binding of PIK3R1 regulatory subunit to phosphopeptides generated by activated receptor tyrosine kinases (Hon et al. 2011). PIK3CA H1047Y, PIK3CA M1043T and PIK3CA M1043V mutants are expected to behave similarly. The arginine residue at position 38 of PIK3CA (R38) is located at a contact site between the ABD and kinase domains of PIK3CA. Substitution of this arginine residue with histidine in PIK3CA R38H mutant is likely to disrupt the interaction between the ABD domain and the kinase domain, causing a conformational change of the kinase domain that leads to increased enzymatic activity (Huang et al. 2007). PIK3CA R38H mutant shows reduced PIK3R1 binding and modestly increased catalytic activity (measured indirectly, via AKT1 phosphorylation) under serum starved conditions (Zhao et al. 2005). PIK3CA R38C, PIK3CA R38G and PIK3CA R38S mutants are expected to behave similarly. Mutations in other conserved domains of PIK3CA, such as membrane-binding C2 domain (Mandelker et al. 2009), have not been annotated as their mechanism of action needs to be further elucidated. Although less common than mutations in PIK3CA, mutations in PIK3R1, encoding the regulatory subunit of PI3K (p85alpha) have been recently described. Mutations mapping to iSH2 and nSH2 domains, the two domains of PIK3R1 involved in the inhibition of PIK3CA, which were shown to result in constitutive activity of PIK3R1 complex, are annotated here. An experimentally studied nSH2 domain mutant is PIK3R1 G376R (Sun et al. 2010). PIK3R1 iSH2 domain mutants, affected by amino acid substitutions and small inframe deletions, PIK3R1 D560Y (Jaiswal et al. 2009), PIK3R1 N564D (Jaiswal et al. 2009), PIK3R1 N564K (Sun et al. 2010), PIK3R1 H450_E451del (Urick et al. 2011), PIK3R1 K459del (Urick et al. 2011), PIK3R1 R574_T576del (Urick et al. 2011) and PIK3R1 Y463_L466del (Urick et al. 2011), were all shown to bind PIK3CA and confer constitutive activity to PI3K complex. PIK3R1 D560H, PIK3R1 R574I and PIK3R1 R574T mutants are expected to behave similarly to functionally characterized D560 and R574 substitution mutants. Co-occurrence of PIK3CA and PIK3R1 mutations has been documented in some tumors, but since it is rare and the exact clinical combinations of PIK3CA and PIK3R1 mutants have not been studied, complexes of PIK3CA mutants with PIK3R1 mutants are not shown (Urick et al. 2011). Although rare, perturbations in genes encoding other isoforms of PI3K subunits have also been reported in cancers. Mutations in PIK3R2, encoding PI3K regulatory subunit isoform p85beta, are found infrequently in endometrial cancers, but have not been functionally studied (Cheung et al. 2011). They are not shown in this context. PIK3CB, encoding PI3K catalytic subunit isoform p110beta, can be overexpressed in cancer, mainly due to genomic gain. Several studies have shown that PTEN deficient cancer cell lines depend on PIK3CB (p110beta) for AKT activation and sustained growth (Wee et al. 2008, Jiang et al. 2010, Chen et al. 2011). PIK3CB activation synergizes with PTEN loss in mouse prostate cancer model (Jia et al. 2008). Mutations in PIK3CB are very rare, have not been functionally studied, and are therefore not shown. Structural studies indicate that, in comparison with PIK3CA (p110alpha), PIK3CB (p110beta) and PIK3CD (p110delta) form additional inhibitory contacts with the regulatory subunit p85alpha, and are therefore probably less prone to mutational activation (Burke et al. 2011). For more information, please refer to recent reviews by Liu et al. 2009 and Vogt et al. 2009.
			REACT_147854 (Reactome)	A variety of inhibitors capable of blocking the phosphoinositide kinase activity of PI3K have been developed. These inhibitors display differential selectivity and inhibit kinase activity of their substrates by distinct mechanisms. For example, the first-generation PI3K inhibitor wortmannin (Wymann et al. 1996) covalently and irreversibly binds all classes of PI3K enzymes, as well as other kinases including mTOR, at a residue critical for catalytic activity. Although wortmannin is precluded from in vivo and clinical use due to its toxicity, it has proven to be a useful tool for in vitro laboratory studies. Newer inhibitors, such as BEZ235, are currently being investigated in Phase I clinical trials. BEZ235 is a dual pan-class I PI3K/mTOR inhibitor that blocks kinase activity by binding competitively to the ATP-binding pocket of these enzymes (Serra et al. 2008, Maira et al. 2008). BGT226 (Chang et al. 2011) and XL765 (Prasad et al. 2011) also inhibits both PI3K class I enzymes and mTOR. Other inhibitors in clinical trials, such as BKM120 (Maira et al. 2012), GDC0941 (Folkes et al. 2008, Junttila et al. 2009) and XL147 (Chakrabarty et al. 2012), are specific for class I PI3Ks and exhibit no activity against mTOR. Current research aims to identify isoform-specific PI3K inhibitors. Small molecule inhibitors that selectively inhibit PIK3CA (p110alpha), e.g. PIK-75 and A66, were used to study the role of p110alpha in signaling and growth of tumor cells (Knight et al. 2006, Sun et al. 2010, Jamieson et al. 2011, Utermark et al. 2012). The PIK3CB (p110beta) specific inhibitor TGX221 has been used in in vitro models of vascular injury (Jackson et al. 2005), and the TGX221 derivative KIN-193 has been shown to block AKT activity and tumor growth in mice with p110beta activation or PTEN loss (Ni et al. 2012). CAL-101 is a PIK3CD (p110delta) specific inhibitor that is being clinically investigated as a therapeutic for lymphoid malignancies (Herman et al. 2010). It is hoped that, in the future, more specific inhibitors, such as those targeting selective PI3K isoforms, will provide optimum treatment while minimizing unwanted side effects. For a recent review, please refer to Liu et al. 2009.
			REACT_147858 (Reactome)	PIP2-binding AKT1 E17K mutants are anchored to the plasma membrane in the absence of PI3K activity and are constitutively phosphorylated on serine S473, presumably by the TORC2 complex (Carpten et al. 2007, Landgraf et al. 2008).
			REACT_147862 (Reactome)	PIP2-bound AKT1 E17K mutant is constitutively phosphorylated on threonine residue T308 (Carpten et al. 2007, Landgraf et al. 2008), presumably by PIP2-bound PDPK1 (Currie et al. 1999).
			REACT_147873 (Reactome)	PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999).
			REACT_147886 (Reactome)	PIP3 generated by PI3K recruits AKT (also known as protein kinase B) to the membrane, through its PH (pleckstrin-homology) domains. The binding of PIP3 to the PH domain of AKT is the rate-limiting step in AKT activation (Scheid et al. 2002). In mammals there are three AKT isoforms (AKT1-3) encoded by three separate genes. The three isoforms share a high degree of amino acid identity and have indistinguishable substrate specificity in vitro. However, isoform-preferred substrates in vivo cannot be ruled out. The relative expression of the three isoforms differs in different mammalian tissues: AKT1 is the predominant isoform in the majority of tissues, AKT2 is the predominant isoform in insulin-responsive tissues, and AKT3 is the predominant isoform in brain and testes. All 3 isoforms are expressed in human and mouse platelets (Yin et al. 2008; O'Brien et al. 2008). Note: all data in the pathway refer to AKT1, which is the most studied.
			REACT_147895 (Reactome)	AKT inhibitors bind AKT and prevent its association with the membrane, thereby blocking AKT activation (Kondapaka et al. 2003, Yap et al. 2011, Berndt et al. 2010). AKT inhibitors annotated here target all AKT isoforms (AKT1, AKT2 and AKT3). None of the annotated inhibitors are AKT E17K mutant specific and none of them have been approved for clinical use. For a recent review, please refer to Liu et al. 2009.
			REACT_147896 (Reactome)	Substitution of glutamic acid with lysine at position 17 of AKT1 results in constitutive plasma membrane localization of AKT1, independent of PI3K activity and PIP3 generation (Carpten et al. 2007). This constitutive plasma membrane targeting of AKT1 E17K mutant is due to an increased affinity for PIP2 (Landgraf et al. 2008).
RPS6KB2			REACT_12485 (Reactome)
THEM4/TRIB3			REACT_12567 (Reactome)
TORC2 complex		mim-catalysis	REACT_12391 (Reactome)
TORC2 complex		mim-catalysis	REACT_147858 (Reactome)
TSC2			REACT_12532 (Reactome)
miR-26A RISC			REACT_147761 (Reactome)
	p-S-AKT:PDPK1:PIP3	Arrow	REACT_147711 (Reactome)
p-S-AKT:PDPK1:PIP3			REACT_12584 (Reactome)
p-S-AKT:PDPK1:PIP3		mim-catalysis	REACT_12584 (Reactome)
	p-S-AKT:PIP3	Arrow	REACT_12391 (Reactome)
p-S-AKT:PIP3			REACT_147711 (Reactome)
	p-S133-CREB1	Arrow	REACT_12597 (Reactome)
	p-S15,S356-RPS6KB2	Arrow	REACT_12485 (Reactome)
	p-S166,S188-MDM2	Arrow	REACT_12537 (Reactome)
	p-S183,T246-AKT1S1	Arrow	REACT_12383 (Reactome)
	p-S196-CASP9(1-416)	Arrow	REACT_12395 (Reactome)
	p-S351-NR4A1	Arrow	REACT_12614 (Reactome)
	p-S473-AKT1 E17K mutant:PIP2	Arrow	REACT_147858 (Reactome)
p-S473-AKT1 E17K mutant:PIP2			REACT_147790 (Reactome)
	p-S9/21-GSK3	Arrow	REACT_12549 (Reactome)
	p-S939,T1462-TSC2	Arrow	REACT_12532 (Reactome)
	p-S99-BAD	Arrow	REACT_12565 (Reactome)
	p-T-AKT	Arrow	REACT_12403 (Reactome)
	p-T-CDKN1A/B	Arrow	REACT_12420 (Reactome)
	p-T23-CHUK	Arrow	REACT_12461 (Reactome)
	p-T308,S473-AKT1 E17K mutant	Arrow	REACT_147862 (Reactome)