Signals controlling un-differentiated states in embryonic stem and cancer cells: Role of the phosphatidylinositol 3′ kinase pathway

Journal of Cellular Physiology

Volumn 229, Issue 10, 2014, Pages 1312-1322

  Voskas, Daniel ^a   Ling, Ling Sunny ^b   Woodgett, James Robert ^b  

^a MOUNT SINAI HOSPITAL   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

GLYCOGEN SYNTHASE KINASE 3; JANUS KINASE; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1; PROTEIN KINASE; PROTEIN KINASE B; RAS PROTEIN; SERUM AND GLUCOCORTICOID REGULATED KINASE; STAT PROTEIN; TRANSFORMING GROWTH FACTOR; UNCLASSIFIED DRUG; WNT PROTEIN;

ARTICLE; CANCER CELL; CELL FUNCTION; CELL MATURATION; EMBRYO; EMBRYONIC STEM CELL; HUMAN; NEOPLASM; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; WNT SIGNALING PATHWAY;

ANIMALS; CELL DIFFERENTIATION; CELL LINEAGE; CELL PROLIFERATION; EMBRYONIC STEM CELLS; HUMANS; MAP KINASE SIGNALING SYSTEM; NEOPLASMS; NEOPLASTIC STEM CELLS; PHOSPHATIDYLINOSITOL 3-KINASE; SIGNAL TRANSDUCTION; WNT SIGNALING PATHWAY;

EID: 84903453693     PISSN: 00219541     EISSN: 10974652     Source Type: Journal    
DOI: 10.1002/jcp.24603     Document Type: Article

References (122)

1. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T. 1994. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77:63-71.
2. Attisano L, Wrana JL. 1996. Signal transduction by members of the transforming growth factor-beta superfamily. Cytokine Growth Factor Rev 7:327-339.
3. Bader AG, Kang S, Zhao L, Vogt PK. 2005. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 5:921-929.
4. Bardeesy N, Cheng KH, Gerger JH, Chu GC, Pahler J, Olson P, Hezel AF, Horner J, Lauwers GY, Hanahan D, DePinho RA. 2006. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev 20:3130-3146.
5. Bayascas JR. 2008. Dissecting the role of the 3-phosphoinositide-dependent protein kinase-1 (PDK1) signaling pathways. Cell Cycle 19:2978-2982.
6. Bechard M, Dalton S. 2009. Subcellular localization of glycogen synthase kinase 3β controls embryonic stem cell self-renewal. Mol Cell Biol 29:2092-2104.
7. Bellacosa A, Testa JR, Stall SP, Tsichlis PN. 1991. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-likeregion. Science 254:274-277.
8. Benchabane H, Hughes EG, Takacs CM, Baird JR, Ahmed Y. 2008. Adenomatous polyposis coli is present near the minimal level required for accurate graded responses to the Wingless morphogen. Development 135:963-971.
9. Boeuf H, Hauss C, Graeve FD, Baran N, Kedinger C. 1997. Leukemia inhibitory factor-dependent transcriptional activation in embryonic stem cells. J Cell Biol 138:1207-1217.
10. Bone HK, Daminao T, Bartlett S, Perry A, Letchford J, Sanchez, Ripoll Y, Nelson AS, Welham MJ. 2009. Involvement of glycogen synthase kinase-3 in regulation of murine embryonic stem cell self-renewal revealed by a series of bisindolymaleimides. Chem Biol 16:15-27.
11. Bone HK, Nelson AS, Goldring CE, Tosh D, Welham MJ. 2011. A novel chemically directed route for the generation of definitive endoderm from human embryonic stem cells based on inhibition of GSK-3. J Cell Sci 124:1992-2000.
12. Boyer LA, Mathur D, Jaenisch R. 2006. Molecular control of pluripotency. Curr Opin Genet Dev 16:455-462.
13. Brugge J, Hung M, Mills MC. 2007. A new mutational AKTivation in the PI3K pathway. Cancer Cell 12:104-107.
14. Burdon T, Stracey C, Chambers I, Nichols J, Smith A. 1999. Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. Dev Biol 210:30-43.
15. Cakir M, Grossman AB. 2009. Targeting MAPK (Ras/ERK) and PI3K/Akt pathways in pituitary tumorigenesis. Expert Opin Ther Targets 13:1121-1134.
16. Canham MA, Sharov AA, Ko MS, Brickman JM. 2010. Functional heterogeneity of embryonic stem cells revealed through translational amplification of an early endodermal transcript. PLoS Biol 8:e1000379.
17. Carlson ME, Conboy IM. 2007. Regulating the Notch pathway in embryonic, adult and old stem cells. Curr Opin Pharmacol 7:303-309.
18. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Boguslawski S, Moses TY, Savage S, Uhlik M, Lin A, Du J, Qian YW, Zeckner DJ, Tucker-Kellogg G, Touchman J, Patel K, Mousses S, Bittner M, Schevitz R, Lai MH, Blanchard KL, Thomas JE. 2007. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448:439-444.
19. Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A. 2003. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113:643-655.
20. Chambers I, Smith A. 2004. Self-renewal of teratocarcinoma and embryonic stem cells. Oncogene 23:7150-7160.
21. Chambers I, Silva J, Colby D, Nichols J, Nijmeijer B, Robertson M, Vrana J, Jones K, Grotewold L, Smith A. 2007. Nanog safeguards pluripotency and mediates germline development. Nature 450:1230-1234.
22. Cohen P, Alessi DR, Cross DA. 1997. PDK1, one of the missing links in insulin signal transduction?. FEBS Lett 410:3-10.
23. Collins FJ, Deak M, Aurthur JS, Armit LJ, Alessi DR. 2003. In vivo role of PIF-binding docking site of PDK1 defined by knock-in mutation. EMBO J 22:4202-4211.
24. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. 1995. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785-789.
25. Davies MA, Stemke-Hale K, Tellez C, Calderone TL, Deng W, Prieto VG, Lazar AJ, Gershenwald JE, Mills GB. 2008. A novel AKT3 mutation in melanoma tumors and cell lines. Br J Cancer 99:1265-1268.
26. Davis LA, Zur Nieden NI. 2008. Mesodermal fate decisions of a stem cell: The Wnt switch. Cell Mol Life Sci 65:2658-2674.
27. Ding VW, Chen RH, McCormick F. 2000. Differential regulation of glycogen synthase kinase 3β by insulin and Wnt signaling. J Biol Chem 275:32475-32481.
28. Doble BW, Woodgett JR. 2003. GSK-3: Tricks of the trade for a multi-tasking kinase. J Cell Sci 116:1175-1186.
29. Doble BW, Patel S, Wood GA, Kockeritz LK, Woodgett JR. 2007. Functional redundancy of GSK-3alpha and GSK-3beta in Wnt/beta-catenin signaling shown by using an allelic series of embryonic stem cell lines. Dev Cell 12:857-871.
30. Dvorak P, Dvorakova D, Hampl A. 2006. Fibroblast growth factor signaling in embryonic and cancer stem cells. FEBS Lett 580:2869-2874.
31. Espinosa L, Ingles-Esteve J, Aguilera C, Bigas A. 2003. Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem 278:32227-32235.
32. Foltz DR, Santiago MC, Berechid BE, Nye JS. 2002. Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol 12:1006-1011.
33. Giles RH, van Es JH, Clevers H. 2003. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 1653:1-24.
34. Gingras AC, Raught B, Sonenberg N. 2001. Regulation of translationinitiation by FRAP/mTOR. Genes Dev 15:807-826.
35. Gomperts BD, Kramer IM, Tatham PER. 2009. Signal transduction. 2nd edition. San Diego: Elsevier, Inc. pp 327-337.
36. Griffiths DS, Li J, Dawson MA, Trotter MW, Cheng YH, Smith AM, Mansfield W, Liu P, Kouzarides T, Nichols J, Bannister AJ, Green AR, Göttgens B. 2011. LIF-independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease. Nat Cell Biol 13:13-21.
37. Gu D, Yu B, Zhao C, Ye W, Lv Q, Hua Z, Ma J, Zhang Y. 2007. The effect of pleiotrophin signaling on adipogenesis. FEBS Lett 581:382-388.
38. Haslam RJ, Koide HB, Hemmings BA. 1993. Pleckstrin domain homology. Nature 363:309-310.
39. Hattori N, Nishino K, Ko YG, Hattori N, Ohgane J, Tanaka S, Shiota K. 2004. Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells. J Biol Chem 279:17063-17069.
40. He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH, Tian Q, Zeng X, He X, Wiedemann LM, Mishina Y, Li L. 2004. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet 36:1117-1121.
41. Hemmings BA, Restuccia DF. 2012. PI3K-PKB/Akt pathway. Cold Spring Harb Persp Biol 4:a011189.
42. Hollander MC, Blumenthal GM, Dennis PA. 2011. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 11:289-301.
43. Huang H, He X. 2008. 2008. Wnt/beta-catenin signaling: New (and old) players and new insights. Curr Opin Cell Biol 20:119-125.
44. Hunter C, Smith R, Cahill DP, Stephens P, Stevens C, Teague J, Greenman C, Edkins S, Bignell G, Davies H, O'Meara S, Parker A, Avis T, Barthorpe S, Brackenbury L, Buck G, Butler A, Clements J, Cole J, Dicks E, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Richardson D, Shepherd R, Small A, Solomon H, Tofts C, Varian J, West S, Widaa S, Yates A, Easton DF, Riggins G, Roy JE, Levine KK, Mueller W, Batchelor TT, Louis DN, Stratton MR, Futreal PA, Wooster R. 2006. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after akylator chemotherapy. Cancer Res 66:3987-3991.
45. Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, Cantley LC, Brugge JS. 2005. Breast cancer-associated PI3KCA mutations are oncogenic in mammary epithelial cells. Cancer Res 65:10992-11000.
46. Ishibe S, Haydu JE, Togawa A, Marlier A, Cantley LG. 2006. Cell confluence regulates hepatocyte growth factor-stimulated cell morphogenesis in a beta-catenin-dependent manner. Mol Cell Biol 26:9232-9243.
47. Ivanova N, Dobrin R, Lu R, Kotenko I, Levorse J, DeCoste C, Schafer X, Lun Y, Lemischka IR. 2006. Dissecting self-renewal in stem cells with RNA interference. Nature 442:533-538.
48. James D, Levine AJ, Besser D, Hammati-Brivanlou A. 2005. TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development 132:1273-1282.
49. Jia J, Amanai K, Wang G, Tang J, Wang B, Jiang J. 2002. Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus. Nature 416:548-552.
50. Jirmanova L, Afanassieff M, Gobert-Gosse S, Markossian S, Savatier P. 2002. Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells. Oncogene 21:5515-5528.
51. Kelly KF, Ng DY, Jayakumaran G, Wood GA, Koide H, Doble BW. 2011. β-catenin enhances Oct-4 activity and reinforces pluripotency through a TCF-independent mechanism. Cell Stem Cell 8:214-227.
52. Kikani CK, Dong LQ, Liu F. 2005. "New"-clear functions of PDK1: Beyond a master kinase in the cytosol? J Cell Biochem 96:1157-1162.
53. Kim JS, Kim BS, Kim J, Park CS, Chung, IY. 2010. The phosphoinositide-3-kinase/Akt pathway mediates the transient increase in Nanog expression during differentiation of F9 cells. Arch Pharm Res 33:1117-1125.
54. Knobbe CB, Lapin V, Suzuki A, Mak TW. 2008. The roles of PTEN in development, physiology, and tumorigenesis in mouse. Oncogene 27:5398-5415.
55. Kobielak K, Stokes N, de la Cruz J, Polak L, Fuchs E. 2007. Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. Proc Natl Acad Sci 104:10063-10068.
56. Kunath T, Saba-El-Leil MK, Almousailleakh M, Wray J, Meloche S, Smith A. 2007. FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development 134:2895-2902.
57. Lawlor MA, Mora A, Ashby PR, Williams MR, Murray-Tait V, Malone L, Prescott AR, Lucocq JM, Alessi DR. 2002. Essential role of PDK1 in regulating cell size and development in mice. EMBO J 21:3728-3738.
58. Lee E, Salic A, Kruger R, Heinrich R, Kirschner MW. 2003. The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol 1:E10.
59. Lemmon MA, Ferguson KM. 2000. Signal-dependent membrane targeting by pleckstrin homology (PH) domains. Biochem J 350:1-18.
60. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R. 1997. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943-1947.
61. Lin Y, Yang Y, Li W, Chen Q, Li J, Pan X, Zhou L, Liu C, Chen C, He J, Cao H, Yao H, Zheng L, Xu X, Xia Z, Ren J, Xiao L, Li L, Shen B, Zhou H, Wang YJ. 2012. Reciprocal regulation of Akt and Oct4 promotes the self-renewal and survival of embryonal carcinoma cells. Mol Cell 48:627-640.
62. Ling LS, Voskas D, Woodgett JR. 2013. Activation of PDK-1 maintains mouse embryonic stem cell self-renewal in a PKB-dependent manner. Oncogene 32:5397-5408.
63. Liu P, Cheng H, Roberts TM, Zhao JJ. 2009. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8:627-643.
64. MacDonald BT, Tamai K, He X. 2009. Wnt/β-catenin signaling: Components, mechanisms, and diseases. Dev Cell 17:9-26.
65. Maes C, Goossens S, Bartunkova S, Drogat B, Coenegrachts L, Stockmans L, Moermans K, Nyabi O, Haigh K, Naessens M, Haenebalcke L, Tuckermann JP, Tjwa M, Carmeliet P, Mandic V, David JP, Behrens A, Nagy A, Carmeliet G, Haigh JJ. 2010. Increased skeletal VEGF enhances β-catenin activity and results in excessively ossified bones. EMBO J 29:424-441.
66. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. 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 10:151-162.
67. Manning BD, Cantley LC. 2007. AKT/PKB signaling: Navigating downstream. Cell 129:1261-1274.
68. Masters TA, Calleja V, Armoogum DA, Marsh RJ, Applebee CJ, Laguerre M, Bain AJ, Larijani B. 2010. Regulation of-phosphoinositide-dependent protein kinase 1 activity by homodimerization in live cells. Sci Signal 3:ra78.
69. Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R, Takahashi K, Okochi H, Okuda A, Matoba R, Sharov AA, Ko MS, Niwa H. 2007. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol 9:625-635.
70. Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T, Yokota T. 1999. STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO J 18:4261-4269.
71. Mayer BJ, Ren R, Clark KL, Baltimore D. 1993. A putative modular domain present in diverse signaling molecules. Cell 73:629-630.
72. McManus EJ, Sakamoto K, Armit LJ, Ronaldson L, Shpiro N, Marquez R, Alessi DR. 2005. Role that phosphorylation of GSK3 plays in insulin and Wnt signaling defined by knockin analysis. EMBO J 24:1571-1583.
73. McNeill H, Woodgett JR. 2010. When pathways collide: Collaboration and connivance among signaling proteins in development. Nat Rev Mol Cell Biol 11:404-413.
74. Ming M, He YY. 2012. PTEN in DNA damage repair. Cancer Lett 319:125-129.
75. Mora A, Komander D, van Aalten DM, Alessi DR. 2004. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol 15:161-170.
76. Ng SS, Mahmoudi T, Danenberg E, Bejaoui I, de Lau W, Korswagen HC, Schutt M, Clevers H. 2009. Phosphatidylinositol 3-kinase signaling does not activate the Wnt cascade. J Biol Chem 284:35308-35313.
77. Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Schöler H, Smith A. 1998. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95:379-391.
78. Niwa H, Burdon T, Chambers I, Smith A. 1998. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev 12:2048-2060.
79. Niwa H, Miyazaki J, Smith AG. 2000. Quantitative expression of Oct3/4 defines differentiation, dedifferentiationor self-renewal of ES cells. Nat Genet 24:372-376.
80. Niwa H. 2007. How is pluripotency determined and maintained? Development 134:635-646.
81. Niwa H, Ogawa K, Shimosato D, Adachi K. 2009. A parallel circuit of LIF signaling pathways maintains pluripotency of mouse ES cells. Nature 460:118-122.
82. Noggle SA, James D, Brivanlou AH. 2005. A molecular basis for human embryonic stem cell pluripotency. Stem Cell Rev 1:111-118.
83. Paling NR, Bone HK, Welham MJ. 2004. Regulation of embryonic stem cell self-renewal by phosphoinositide 3-kinase-dependent signaling. J Biol Chem 279:48063-48070.
84. Pan G, Thomson JA. 2007. Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res 17:42-49.
85. Patel S, Doble B, Woodgett JR. 2004. Glycogen synthase-3 in insulin and Wnt signaling: A double-edged sword. Biochem Soc Trans 32:803-808.
86. Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, Huff CA, Beachy PA, Watkins DN, Matsui W. 2007. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci 104:4048-4053.
87. Price MA, Kalderon D. 2002. Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by glycogen synthase kinase 3 and casein kinase 1. Cell 108:823-835.
88. Qi X, Li TG, Hao J, Hu J, Wang J, Simmons H, Miura S, Mishina Y, Zhao GQ. 2004. BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways. Proc Natl Acad Sci 101:6027-6032.
89. Samuels Y, Velculescu VE. 2004. Oncogenic mutations of PI3KCA in human cancers. Cell Cycle 3:1221-1224.
90. Samuels Y, Diaz LA, Jr, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, Rago C, Huso DL, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. 2005. Mutant PI3KCA promotes cell growth and invasion of human cancer cells. Cancer Cell 7:561-573.
91. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. 2005. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098-1101.
92. Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. 2004. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10:55-63.
93. Saunders FR, Wallace HM. 2007. Polyamine metabolism and cancer prevention. Biochem Soc Trans 35:364-368.
94. Scheid MP, Woodgett JR. 2003. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett 546:108-112.
95. Sebolt-Leopold JS, Herrera R. 2004. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4:937-947.
96. Singh AM, Reynolds D, Cliff T, Ohtsuka S, Mattheyses AL, Sun Y, Menendez L, Kulik M, Dalton S. 2012. Signaling network crosstalk in human pluripotent cells: A Smad2/3-regulated switch that controls the balance between self-renewal and differentiation. Cell Stem Cell 10:312-326.
97. Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW. 1998. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95:29-39.
98. Stambolic V, Woodgett JR. 2006. Functional distinctions of protein kinase B/Akt isoforms defined by their influence on cell migration. Trends Cell Biol 16:461-466.
99. Stiles B, Gilman V, Khanzenzon N, Lesche R, Li A, Qiao R, Liu X, Wu H. 2002. Essential role of AKT-1/protein kinase B alpha in PTEN-controlled tumorigenesis. Mol Cell Biol 22:3842-3851.
100. Storm MP, Kumpfmueller B, Thompson B, Kolde R, Vilo J, Hummel O, Schulz H, Welham MJ. 2014. Characterization of the phosphoinositide 3-kinase-dependent transcriptome in murine embryonic stem cells: Identification of novel regulators of pluripotency. Stem Cells 27:764-775.
101. Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, Gavrilova N, Mueller B, Liu X, Wu H. 1999. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3, 4, 5, -trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci 96:6199-6204.
102. Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes, I, Ho A, Wakeham A, Itie A, Khoo W, Fukumoto M, Mak TW. 1998. High cancer susceptibility and embryonic lethality associated with mutation of thePTEN tumor suppressor gene in mice. Curr Biol 8:1169-1178.
103. Suzuki A, Nakano T, Mak TW, Sasaki T. 2008. Portrait of PTEN: Messages from mutant mice. Cancer Sci 99:209-213.
104. Takahashi K, Nakagawa M, Young SG, Yamanaka S. 2005. Differential membrane localization of ERas and Rheb, two Ras-related proteins involved in the phosphatidylinositol 3-kinase/mTOR pathway. J Biol Chem 280:32768-32774.
105. Tessier M, Woodgett, JR. 2006a. Serum and glucocorticoid-regulated protein kinases: Variations on a theme. J Cell Biochem 98:1391-1407.
106. Tessier M, Woodgett JR. 2006b. Role of the Phox homology domain and phosphorylation in activation of serum and glucocorticoid-regulated kinase-3. J Biol Chem 281:23978-23989.
107. Tominaga Y, Tamguney T, Kolesnichenko M, Bilanges B, Sokoe D. 2005. Translational deregulation in PDK1-/- embryonic stem cells. Mol Cell Biol 25:8465-8475.
108. Turner DA, Trott J, Hayward P, Rué P, Martinez-Arias A. 2014. An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells. BioRxiv DOI: 10.1101/000653.
109. Vallier L, Alexander M, Pedersen RA. 2005. Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J Cell Sci 118:4495-4509.
110. Voskas D, Ling LS, Woodgett JR. 2010. Does GSK-3 provide a shortcut for PI3K activation of Wnt signaling? F1000. Biol Rep 2:82.
111. Watanabe S, Umehara H, Murayama K, Okabe M, Kimura T, Nakano T. 2006. Activation of Akt signaling is sufficient to maintain pluripotency in mouse and primate embryonic stem cells. Oncogene 25:2697-2707.
112. Welham MJ, Kingham E, Bone HK. 2007. Phosphoinositide 3-kinases and regulation of embryonic stem cell fate. Biochem Soc Trans 35:225-228.
113. Welham MJ, Kingham E, Sanchez-Ripoll Y, Kumpfmueller B, Storm M, Bone H. 2011. Controlling embryonic stem cell proliferation and pluripotency: The role of PI3K- and GSK-3-dependent signaling. Biochem Soc Trans 39:674-678.
114. Williams MR, Authur JS, Balendra A, van der Kaay J, Poli V, Cohen P, Alessi DR. 2002. The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells. Curr Biol 10:439-448.
115. Wong KK, Engelman JA, Cantley LC. 2010. Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 20:87-90.
116. Woodgett JR. 2005. Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol 17:150-157.
117. Wu R, Hendrix-Lucas N, Kuick R, Zhai Y, Schwartz DR, Akyol A, Hanash S, Misek DE, Katabuchi H, Williams BO, Fearon ER, Cho KR. 2007. Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways. Cancer Cell 11:321-333.
118. Wu G, Huang H, Garcia Abreu J, He X. 2009. Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6. PLoS ONE 4:e4926.
119. Wu D, Pan W. 2010. GSK3: A multifaceted kinase in Wnt signaling. Trends Biochem Sci 35:161-168.
120. Ying QL, Nichols J, Chambers I, Smith A. 2003. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115:281-292.
121. Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A. 2008. The ground state of embryonic stem cell self-renewal. Nature 453:519-523.
122. Yuan TL, Cantley LC. 2008. PI3K pathway alterations in cancer: Variations on a theme. Oncogene 27:5497-5510.