AKT/PKB Signaling: Navigating Downstream

Accili, 2004, FoxOs at the crossroads of cellular metabolism, differentiation, and transformation, Cell, 117, 421, 10.1016/S0092-8674(04)00452-0

Ackah, 2005, Akt1/protein kinase Balpha is critical for ischemic and VEGF-mediated angiogenesis, J. Clin. Invest., 115, 2119, 10.1172/JCI24726

Alessi, 1996, Mechanism of activation of protein kinase B by insulin and IGF-1, EMBO J., 15, 6541, 10.1002/j.1460-2075.1996.tb01045.x

Alessi, 1996, Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase, FEBS Lett., 399, 333, 10.1016/S0014-5793(96)01370-1

Andjelkovic, 1997, Role of translocation in the activation and function of protein kinase B, J. Biol. Chem., 272, 31515, 10.1074/jbc.272.50.31515

Arboleda, 2003, Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells, Cancer Res., 63, 196

Bai, 2007, Dissecting multiple steps of GLUT4 trafficking and identifying the sites of insulin action, Cell Metab., 5, 47, 10.1016/j.cmet.2006.11.013

Bellacosa, 1991, A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region, Science, 254, 274

Bellacosa, 2005, Activation of AKT kinases in cancer: implications for therapeutic targeting, Adv. Cancer Res., 94, 29, 10.1016/S0065-230X(05)94002-5

Berwick, 2002, The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes, J. Biol. Chem., 277, 33895, 10.1074/jbc.M204681200

Berwick, 2004, Protein kinase B phosphorylation of PIKfyve regulates the trafficking of GLUT4 vesicles, J. Cell Sci., 117, 5985, 10.1242/jcs.01517

Brognard, 2007, PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms, Mol. Cell, 25, 917, 10.1016/j.molcel.2007.02.017

Brunet, 1999, Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor, Cell, 96, 857, 10.1016/S0092-8674(00)80595-4

Brunet, 2001, Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a), Mol. Cell. Biol., 21, 952, 10.1128/MCB.21.3.952-965.2001

Cai, 2006, Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning, J. Cell Biol., 173, 279, 10.1083/jcb.200507119

Calera, 1998, Insulin increases the association of Akt-2 with Glut4-containing vesicles, J. Biol. Chem., 273, 7201, 10.1074/jbc.273.13.7201

Cardone, 1998, Regulation of cell death protease caspase-9 by phosphorylation, Science, 282, 1318, 10.1126/science.282.5392.1318

Chiang, 2005, Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase, J. Biol. Chem., 280, 25485, 10.1074/jbc.M501707200

Collins, 2003, In vivo role of the PIF-binding docking site of PDK1 defined by knock-in mutation, EMBO J., 22, 4202, 10.1093/emboj/cdg407

Cross, 1995, Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B, Nature, 378, 785, 10.1038/378785a0

Datta, 1997, Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery, Cell, 91, 231, 10.1016/S0092-8674(00)80405-5

Datta, 2000, 14–3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation, Mol. Cell, 6, 41, 10.1016/S1097-2765(05)00012-2

Datta, 2002, Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis, Dev. Cell, 3, 631, 10.1016/S1534-5807(02)00326-X

delPeso, 1997, Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt, Science, 278, 687, 10.1126/science.278.5338.687

Diehl, 1998, Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization, Genes Dev., 12, 3499, 10.1101/gad.12.22.3499

Dijkers, 2002, FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity, J. Cell Biol., 156, 531, 10.1083/jcb.200108084

Dimmeler, 1999, Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation, Nature, 399, 601, 10.1038/21224

Dong, 2004, Tsc2 is not a critical target of Akt during normal Drosophila development, Genes Dev., 18, 2479, 10.1101/gad.1240504

Dummler, 2007, Physiological roles of PKB/Akt isoforms in development and disease, Biochem. Soc. Trans., 35, 231, 10.1042/BST0350231

Edinger, 2002, Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake, Mol. Biol. Cell, 13, 2276, 10.1091/mbc.01-12-0584

Eguez, 2005, Full intracellular retention of GLUT4 requires AS160 Rab GTPase activating protein, Cell Metab., 2, 263, 10.1016/j.cmet.2005.09.005

Elstrom, 2004, Akt stimulates aerobic glycolysis in cancer cells, Cancer Res., 64, 3892, 10.1158/0008-5472.CAN-03-2904

Engelman, 2006, The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism, Nat. Rev. Genet., 7, 606, 10.1038/nrg1879

Frame, 2001, GSK3 takes centre stage more than 20 years after its discovery, Biochem. J., 359, 1, 10.1042/bj3590001

Fulton, 1999, Regulation of endothelium-derived nitric oxide production by the protein kinase Akt, Nature, 399, 597, 10.1038/21218

Gao, 2001, TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth, Genes Dev., 15, 1383, 10.1101/gad.901101

Goncharova, 2002, Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation: a role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM), J. Biochem. (Tokyo), 277, 30958

Gordan, 2007, Hypoxia-inducible factors: central regulators of the tumor phenotype, Curr. Opin. Genet. Dev., 17, 71, 10.1016/j.gde.2006.12.006

Goswami, 2005, Binding and phosphorylation of par-4 by akt is essential for cancer cell survival, Mol. Cell, 20, 33, 10.1016/j.molcel.2005.08.016

Guertin, 2006, Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1, Dev. Cell, 11, 859, 10.1016/j.devcel.2006.10.007

Harthill, 2002, Regulation of the 14–3-3-binding protein p39 by growth factors and nutrients in rat PC12 pheochromocytoma cells, Biochem. J., 368, 565, 10.1042/bj20020838

Heron-Milhavet, 2006, Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding, Mol. Cell. Biol., 26, 8267, 10.1128/MCB.00201-06

Holz, 2005, Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase, J. Biol. Chem., 280, 26089, 10.1074/jbc.M504045200

Hutchinson, 2004, Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion, Cancer Res., 64, 3171, 10.1158/0008-5472.CAN-03-3465

Hutti, 2004, A rapid method for determining protein kinase phosphorylation specificity, Nat. Methods, 1, 27, 10.1038/nmeth708

Inoki, 2002, TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling, Nat. Cell Biol., 4, 648, 10.1038/ncb839

Irie, 2005, Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition, J. Cell Biol., 171, 1023, 10.1083/jcb.200505087

Jacinto, 2006, SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity, Cell, 127, 125, 10.1016/j.cell.2006.08.033

Jones, 1991, Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily, Proc. Natl. Acad. Sci. USA, 88, 4171, 10.1073/pnas.88.10.4171

Kandel, 2002, Activation of Akt/protein kinase B overcomes a G(2)/m cell cycle checkpoint induced by DNA damage, Mol. Cell. Biol., 22, 7831, 10.1128/MCB.22.22.7831-7841.2002

Katome, 2003, Use of RNA interference-mediated gene silencing and adenoviral overexpression to elucidate the roles of AKT/protein kinase B isoforms in insulin actions, J. Biol. Chem., 278, 28312, 10.1074/jbc.M302094200

Kim, 2001, Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1, Mol. Cell. Biol., 21, 893, 10.1128/MCB.21.3.893-901.2001

King, 2004, Inhibition of Chk1 by activated PKB/Akt, Cell Cycle, 3, 634, 10.4161/cc.3.5.894

Kohn, 1996, Expression of a constitutively active Akt Ser/Thr kinase in 3T3–L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation, J. Biol. Chem., 271, 31372, 10.1074/jbc.271.49.31372

Kovacina, 2003, Identification of a proline-rich Akt substrate as a 14–3-3 binding partner, J. Biol. Chem., 278, 10189, 10.1074/jbc.M210837200

Li, 2007, Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1α transcription coactivator, Nature, 10.1038/nature05861

Liang, 2002, PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest, Nat. Med., 8, 1153, 10.1038/nm761

Lum, 2007, The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis, Genes Dev., 21, 1037, 10.1101/gad.1529107

Majumder, 2005, Akt-regulated pathways in prostate cancer, Oncogene, 24, 7465, 10.1038/sj.onc.1209096

Majumder, 2004, mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways, Nat. Med., 10, 594, 10.1038/nm1052

Mamane, 2004, eIF4E–from translation to transformation, Oncogene, 23, 3172, 10.1038/sj.onc.1207549

Manning, 2003, Rheb fills a GAP between TSC and TOR, Trends Biochem. Sci., 28, 573, 10.1016/j.tibs.2003.09.003

Manning, 2002, Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway, Mol. Cell, 10, 151, 10.1016/S1097-2765(02)00568-3

Marte, 1997, PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond, Trends Biochem. Sci., 22, 355, 10.1016/S0968-0004(97)01097-9

Maurer, 2006, Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1, Mol. Cell, 21, 749, 10.1016/j.molcel.2006.02.009

Mayo, 2001, A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus, Proc. Natl. Acad. Sci. USA, 98, 11598, 10.1073/pnas.181181198

McManus, 2004, The in vivo role of PtdIns(3,4,5)P(3) binding to PDK1 PH domain defined by knockin mutation, EMBO J., 23, 2071, 10.1038/sj.emboj.7600218

McManus, 2005, Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis, EMBO J., 24, 1571, 10.1038/sj.emboj.7600633

Medema, 2000, AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1, Nature, 404, 782, 10.1038/35008115

Morbidelli, 2003, Role of nitric oxide in the modulation of angiogenesis, Curr. Pharm. Des., 9, 521, 10.2174/1381612033391405

Obata, 2000, Use of peptide and protein library screening to define optimal substrate motifs for Akt/PKB, J. Biol. Chem., 275, 108, 10.1074/jbc.M005497200

Olsson, 2006, VEGF receptor signalling - in control of vascular function, Nat. Rev. Mol. Cell Biol., 7, 359, 10.1038/nrm1911

Ozes, 1999, NF-κB activation by tumour necrosis factor requires the Akt serine-threonine kinase, Nature, 401, 82, 10.1038/43466

Paradis, 1998, Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor, Genes Dev., 12, 2488, 10.1101/gad.12.16.2488

Plas, 2005, Akt-dependent transformation: there is more to growth than just surviving, Oncogene, 24, 7435, 10.1038/sj.onc.1209097

Potter, 2002, Akt regulates growth by directly phosphorylating Tsc2, Nat. Cell Biol., 4, 658, 10.1038/ncb840

Puc, 2005, Lack of PTEN sequesters CHK1 and initiates genetic instability, Cancer Cell, 7, 193, 10.1016/j.ccr.2005.01.009

Robey, 2006, Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt, Oncogene, 25, 4683, 10.1038/sj.onc.1209595

Romashkova, 1999, NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling, Nature, 401, 86, 10.1038/43474

Rommel, 1999, Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt, Science, 286, 1738, 10.1126/science.286.5445.1738

Sabatini, 2006, mTOR and cancer: insights into a complex relationship, Nat. Rev. Cancer, 6, 729, 10.1038/nrc1974

Sancak, 2007, PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase, Mol. Cell, 25, 903, 10.1016/j.molcel.2007.03.003

Sano, 2003, Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation, J. Biol. Chem., 278, 14599, 10.1074/jbc.C300063200

Sapkota, 2007, BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo, Biochem. J., 401, 29, 10.1042/BJ20061088

Scott, 1998, Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway, Proc. Natl. Acad. Sci. USA, 95, 7772, 10.1073/pnas.95.13.7772

Sekimoto, 2004, 14–3-3 suppresses the nuclear localization of threonine 157-phosphorylated p27(Kip1), EMBO J., 23, 1934, 10.1038/sj.emboj.7600198

Sekulic, 2000, A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells, Cancer Res., 60, 3504

Semenza, 2003, Targeting HIF-1 for cancer therapy, Nat. Rev. Cancer, 3, 721, 10.1038/nrc1187

Semenza, 1994, Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1, J. Biol. Chem., 269, 23757, 10.1016/S0021-9258(17)31580-6

Shin, 2002, PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization, Nat. Med., 8, 1145, 10.1038/nm759

Shtivelman, 2002, A role for PI 3-kinase and PKB activity in the G2/M phase of the cell cycle, Curr. Biol., 12, 919, 10.1016/S0960-9822(02)00843-6

Skeen, 2006, Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner, Cancer Cell, 10, 269, 10.1016/j.ccr.2006.08.022

Staal, 1987, Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma, Proc. Natl. Acad. Sci. USA, 84, 5034, 10.1073/pnas.84.14.5034

Sundqvist, 2005, Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF-FBW7, Cell Metab., 1, 379, 10.1016/j.cmet.2005.04.010

Taha, 1999, Opposite translational control of GLUT1 and GLUT4 glucose transporter mRNAs in response to insulin. Role of mammalian target of rapamycin, protein kinase b, and phosphatidylinositol 3-kinase in GLUT1 mRNA translation, J. Biol. Chem., 274, 33085, 10.1074/jbc.274.46.33085

Tapon, 2001, The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation, Cell, 105, 345, 10.1016/S0092-8674(01)00332-4

Tran, 2003, The many forks in FOXO's road, Sci. STKE, 2003, RE5, 10.1126/stke.2003.172.re5

Vander Haar, 2007, Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40, Nat. Cell Biol., 9, 316, 10.1038/ncb1547

Viglietto, 2002, Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer, Nat. Med., 8, 1136, 10.1038/nm762

Villunger, 2003, p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa, Science, 302, 1036, 10.1126/science.1090072

Wei, 2005, The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase, Cancer Cell, 8, 25, 10.1016/j.ccr.2005.06.005

Welcker, 2003, Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation, Mol. Cell, 12, 381, 10.1016/S1097-2765(03)00287-9

Wullschleger, 2006, TOR signaling in growth and metabolism, Cell, 124, 471, 10.1016/j.cell.2006.01.016

Yaffe, 2001, A motif-based profile scanning approach for genome-wide prediction of signaling pathways, Nat. Biotechnol., 19, 348, 10.1038/86737

Yang, 2002, Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP, Nat. Struct. Biol., 9, 940, 10.1038/nsb870

Yeh, 2004, A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells, Nat. Cell Biol., 6, 308, 10.1038/ncb1110

Yoeli-Lerner, 2005, Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT, Mol. Cell, 20, 539, 10.1016/j.molcel.2005.10.033

Zelzer, 1998, Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT, EMBO J., 17, 5085, 10.1093/emboj/17.17.5085

Zhang, 2002, Phosphoprotein analysis using antibodies broadly reactive against phosphorylated motifs, J. Biol. Chem., 277, 39379, 10.1074/jbc.M206399200

Zhang, 2006, S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt, Mol. Cell, 24, 185, 10.1016/j.molcel.2006.09.019

Zhou, 2001, Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells, Nat. Cell Biol., 3, 245, 10.1038/35060032

Zhou, 2001, HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation, Nat. Cell Biol., 3, 973, 10.1038/ncb1101-973

Zhou, 2006, Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration, J. Biol. Chem., 281, 36443, 10.1074/jbc.M600788200

Zimmermann, 1999, Phosphorylation and regulation of Raf by Akt (protein kinase B), Science, 286, 1741, 10.1126/science.286.5445.1741