Major Physiological Signaling Pathways in the Regulation of Cell Proliferation and Survival

  • Huifang TangEmail author
  • Gongda Xue
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 249)


Multiple signaling pathways regulate cell proliferation and survival and are therefore important for maintaining homeostasis of development. The balance between cell growth and death is achieved through orchestrated signal transduction pathways mediated by complex functional interactions between signaling axes, among which, PI3K/Akt and Ras/MAPK as well as JAK/STAT play a dominant role in promoting cell proliferation, differentiation, and survival. In clinical cancer therapies, drug resistance is the major challenge that occurs in almost all targeted therapeutic strategies. Recent advances in research have suggested that the intrinsic pro-survival signaling crosstalk is the driving force in acquired resistance to a targeted therapy, which may be abolished by interfering with the cross-reacting network.


Apoptosis Cell cycle Drug resistance JAK/STAT Lung cancer Melanoma mTOR/PI3K/Akt Proliferation Ras/MAPK Signaling crosstalk 



This work was supported by National Natural Science Foundation of China Grant 381570056.


  1. Aberg E, Torgersen KM, Johansen B, Keyse SM, Perander M, Seternes OM (2009) Docking of PRAK/MK5 to the atypical MAPKs ERK3 and ERK4 defines a novel MAPK interaction motif. J Biol Chem 284:19392–19401. doi: 10.1074/jbc.M109.023283 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Al-Mahdi R, Babteen N, Thillai K, Holt M, Johansen B, Wetting HL, Seternes OM, Wells CM (2015) A novel role for atypical MAPK kinase ERK3 in regulating breast cancer cell morphology and migration. Cell Adh Migr 9:483–494. doi: 10.1080/19336918.2015.1112485 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Anjum R, Blenis J (2008) The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol 9:747–758. doi: 10.1038/nrm2509 CrossRefPubMedGoogle Scholar
  4. Arthur JS (2008) MSK activation and physiological roles. Front Biosci 13:5866–5879CrossRefGoogle Scholar
  5. Borisov N, Aksamitiene E, Kiyatkin A, Legewie S, Berkhout J, Maiwald T, Kaimachnikov NP, Timmer J, Hoek JB, Kholodenko BN (2009) Systems-level interactions between insulin-EGF networks amplify mitogenic signaling. Mol Syst Biol 5:256. doi: 10.1038/msb.2009.19 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bozulic L, Surucu B, Hynx D, Hemmings BA (2008) PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol Cell 30:203–213. doi: 10.1016/j.molcel.2008.02.024 CrossRefPubMedGoogle Scholar
  7. Britschgi A, Andraos R, Brinkhaus H, Klebba I, Romanet V, Muller U, Murakami M, Radimerski T, Bentires-Alj M (2012) JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell 22:796–811. doi: 10.1016/j.ccr.2012.10.023 CrossRefPubMedGoogle Scholar
  8. Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75:50–83. doi: 10.1128/MMBR.00031-10 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Carriere A, Cargnello M, Julien LA, Gao H, Bonneil E, Thibault P, Roux PP (2008a) Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr Biol 18:1269–1277. doi: 10.1016/j.cub.2008.07.078 CrossRefPubMedGoogle Scholar
  10. Carriere A, Ray H, Blenis J, Roux PP (2008b) The RSK factors of activating the Ras/MAPK signaling cascade. Front Biosci 13:4258–4275CrossRefGoogle Scholar
  11. Carriere A, Romeo Y, Acosta-Jaquez HA, Moreau J, Bonneil E, Thibault P, Fingar DC, Roux PP (2011) ERK1/2 phosphorylate Raptor to promote Ras-dependent activation of mTOR complex 1 (mTORC1). J Biol Chem 286:567–577. doi: 10.1074/jbc.M110.159046 CrossRefPubMedGoogle Scholar
  12. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, Majumder PK, Baselga J, Rosen N (2011) AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19:58–71. doi: 10.1016/j.ccr.2010.10.031 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410:37–40. doi: 10.1038/35065000 CrossRefPubMedGoogle Scholar
  14. Chen R, Kim O, Yang J, Sato K, Eisenmann KM, McCarthy J, Chen H, Qiu Y (2001) Regulation of Akt/PKB activation by tyrosine phosphorylation. J Biol Chem 276:31858–31862. doi: 10.1074/jbc.C100271200 CrossRefPubMedGoogle Scholar
  15. Chen CH, Wang WJ, Kuo JC, Tsai HC, Lin JR, Chang ZF, Chen RH (2005) Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK. EMBO J 24:294–304. doi: 10.1038/sj.emboj.7600510 CrossRefPubMedGoogle Scholar
  16. Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD, Wang LH (2007) Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res 67:1979–1987. doi: 10.1158/0008-5472.CAN-06-1479 CrossRefPubMedGoogle Scholar
  17. Chung J, Uchida E, Grammer TC, Blenis J (1997) STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. Mol Cell Biol 17:6508–6516CrossRefGoogle Scholar
  18. Cohen P, Frame S (2001) The renaissance of GSK3. Nat Rev Mol Cell Biol 2:769–776. doi: 10.1038/35096075 CrossRefPubMedGoogle Scholar
  19. Coulombe P, Meloche S (2007) Atypical mitogen-activated protein kinases: structure, regulation and functions. Biochim Biophys Acta 1773:1376–1387. doi: 10.1016/j.bbamcr.2006.11.001 CrossRefPubMedGoogle Scholar
  20. 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. doi: 10.1038/378785a0 CrossRefPubMedGoogle Scholar
  21. Cybulski N, Hall MN (2009) TOR complex 2: a signaling pathway of its own. Trends Biochem Sci 34:620–627. doi: 10.1016/j.tibs.2009.09.004 CrossRefPubMedGoogle Scholar
  22. De la Mota-Peynado A, Chernoff J, Beeser A (2011) Identification of the atypical MAPK Erk3 as a novel substrate for p21-activated kinase (Pak) activity. J Biol Chem 286:13603–13611. doi: 10.1074/jbc.M110.181743 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, Bartholomeusz G, Li Y, Pan Y, Li Z, Bargou RC, Qin J, Lai CC, Tsai FJ, Tsai CH, Hung MC (2005) Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 19:159–170. doi: 10.1016/j.molcel.2005.06.009 CrossRefPubMedGoogle Scholar
  24. Drew BA, Burow ME, Beckman BS (2012) MEK5/ERK5 pathway: the first fifteen years. Biochim Biophys Acta 1825:37–48. doi: 10.1016/j.bbcan.2011.10.002 CrossRefPubMedGoogle Scholar
  25. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516. doi: 10.1080/01926230701320337 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619. doi: 10.1038/nrg1879 CrossRefPubMedGoogle Scholar
  27. Fayard E, Xue G, Parcellier A, Bozulic L, Hemmings BA (2010) Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway. Curr Top Microbiol Immunol 346:31–56. doi: 10.1007/82_2010_58 CrossRefPubMedGoogle Scholar
  28. Figueroa C, Tarras S, Taylor J, Vojtek AB (2003) Akt2 negatively regulates assembly of the POSH-MLK-JNK signaling complex. J Biol Chem 278:47922–47927. doi: 10.1074/jbc.M307357200 CrossRefPubMedGoogle Scholar
  29. Fruman DA, Rommel C (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 13:140–156. doi: 10.1038/nrd4204 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Gaestel M (2015) MAPK-activated protein kinases (MKs): novel insights and challenges. Front Cell Dev Biol 3:88. doi: 10.3389/fcell.2015.00088 CrossRefPubMedGoogle Scholar
  31. Garcia-Echeverria C, Sellers WR (2008) Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27:5511–5526. doi: 10.1038/onc.2008.246 CrossRefPubMedGoogle Scholar
  32. Greer EL, Brunet A (2005) FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24:7410–7425. doi: 10.1038/sj.onc.1209086 CrossRefPubMedGoogle Scholar
  33. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70CrossRefGoogle Scholar
  34. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi: 10.1016/j.cell.2011.02.013 CrossRefGoogle Scholar
  35. Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ (2001) p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci U S A 98:9666–9670. doi: 10.1073/pnas.171301998 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Hartwell LH, Kastan MB (1994) Cell cycle control and cancer. Science 266:1821–1828CrossRefGoogle Scholar
  37. Hayashi M, Lee JD (2004) Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice. J Mol Med (Berl) 82:800–808. doi: 10.1007/s00109-004-0602-8 CrossRefGoogle Scholar
  38. Haynes MP, Li L, Sinha D, Russell KS, Hisamoto K, Baron R, Collinge M, Sessa WC, Bender JR (2003) Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen. J Biol Chem 278:2118–2123. doi: 10.1074/jbc.M210828200 CrossRefPubMedGoogle Scholar
  39. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB (2005) Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4:988–1004. doi: 10.1038/nrd1902 CrossRefPubMedGoogle Scholar
  40. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13:714–726. doi: 10.1038/nrc3599 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Holz MK, Ballif BA, Gygi SP, Blenis J (2005) mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123:569–580. doi: 10.1016/j.cell.2005.10.024 CrossRefPubMedGoogle Scholar
  42. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB, Marto JA, Sabatini DM (2011) The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332:1317–1322. doi: 10.1126/science.1199498 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Huang J, Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37:217–222. doi: 10.1042/BST0370217 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657. doi: 10.1038/ncb839 CrossRefPubMedGoogle Scholar
  45. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126:955–968. doi: 10.1016/j.cell.2006.06.055 CrossRefPubMedGoogle Scholar
  46. Jastrzebski K, Hannan KM, Tchoubrieva EB, Hannan RD, Pearson RB (2007) Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors 25:209–226. doi: 10.1080/08977190701779101 CrossRefPubMedGoogle Scholar
  47. Ji M, Guan H, Gao C, Shi B, Hou P (2011) Highly frequent promoter methylation and PIK3CA amplification in non-small cell lung cancer (NSCLC). BMC Cancer 11:147. doi: 10.1186/1471-2407-11-147 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Jin HO, Lee YH, Park JA, Kim JH, Hong SE, Kim HA, Kim EK, Noh WC, Kim BH, Ye SK, Chang YH, Hong SI, Hong YJ, Park IC, Lee JK (2014) Blockage of Stat3 enhances the sensitivity of NSCLC cells to PI3K/mTOR inhibition. Biochem Biophys Res Commun 444:502–508. doi: 10.1016/j.bbrc.2014.01.086 CrossRefPubMedGoogle Scholar
  49. Kim AH, Khursigara G, Sun X, Franke TF, Chao MV (2001) Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol 21:893–901. doi: 10.1128/MCB.21.3.893-901.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  50. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293. doi: 10.1016/j.cell.2012.03.017 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Lee H, Khanal Lamichhane A, Garraffo HM, Kwon-Chung KJ, Chang YC (2012) Involvement of PDK1, PKC and TOR signalling pathways in basal fluconazole tolerance in Cryptococcus neoformans. Mol Microbiol 84:130–146. doi: 10.1111/j.1365-2958.2012.08016.x CrossRefPubMedPubMedCentralGoogle Scholar
  52. Levy DE, Darnell JE Jr (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662. doi: 10.1038/nrm909 CrossRefPubMedGoogle Scholar
  53. Long W, Foulds CE, Qin J, Liu J, Ding C, Lonard DM, Solis LM, Wistuba II, Qin J, Tsai SY, Tsai MJ, O’Malley BW (2012) ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion. J Clin Invest 122:1869–1880. doi: 10.1172/JCI61492 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121:179–193. doi: 10.1016/j.cell.2005.02.031 CrossRefPubMedGoogle Scholar
  55. Magnuson B, Ekim B, Fingar DC (2012) Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J 441:1–21. doi: 10.1042/BJ20110892 CrossRefPubMedGoogle Scholar
  56. Mahajan K, Mahajan NP (2015) ACK1/TNK2 tyrosine kinase: molecular signaling and evolving role in cancers. Oncogene 34:4162–4167. doi: 10.1038/onc.2014.350 CrossRefPubMedGoogle Scholar
  57. Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schonbrunn E, Sebti SM, Earp HS, Mahajan NP (2010) Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One 5:e9646. doi: 10.1371/journal.pone.0009646 CrossRefPubMedPubMedCentralGoogle Scholar
  58. Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274. doi: 10.1016/j.cell.2007.06.009 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912–1934. doi: 10.1126/science.1075762 CrossRefPubMedGoogle Scholar
  60. Marsit CJ, Zheng S, Aldape K, Hinds PW, Nelson HH, Wiencke JK, Kelsey KT (2005) PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol 36:768–776. doi: 10.1016/j.humpath.2005.05.006 CrossRefPubMedGoogle Scholar
  61. Mayer IA, Arteaga CL (2016) The PI3K/AKT pathway as a target for cancer treatment. Annu Rev Med 67:11–28. doi: 10.1146/annurev-med-062913-051343 CrossRefPubMedGoogle Scholar
  62. Moelling K, Schad K, Bosse M, Zimmermann S, Schweneker M (2002) Regulation of Raf-Akt cross-talk. J Biol Chem 277:31099–31106. doi: 10.1074/jbc.M111974200 CrossRefPubMedGoogle Scholar
  63. Nakayama KI, Nakayama K (2006) Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6:369–381. doi: 10.1038/nrc1881 CrossRefPubMedGoogle Scholar
  64. Ou YH, Torres M, Ram R, Formstecher E, Roland C, Cheng T, Brekken R, Wurz R, Tasker A, Polverino T, Tan SL, White MA (2011) TBK1 directly engages Akt/PKB survival signaling to support oncogenic transformation. Mol Cell 41:458–470. doi: 10.1016/j.molcel.2011.01.019 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Pearce LR, Komander D, Alessi DR (2010) The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 11:9–22. doi: 10.1038/nrm2822 CrossRefPubMedGoogle Scholar
  66. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22:153–183. doi: 10.1210/edrv.22.2.0428 CrossRefPubMedGoogle Scholar
  67. Posch C, Moslehi H, Feeney L, Green GA, Ebaee A, Feichtenschlager V, Chong K, Peng L, Dimon MT, Phillips T, Daud AI, McCalmont TH, LeBoit PE, Ortiz-Urda S (2013) Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. Proc Natl Acad Sci U S A 110:4015–4020. doi: 10.1073/pnas.1216013110 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Qi M, Elion EA (2005) MAP kinase pathways. J Cell Sci 118:3569–3572. doi: 10.1242/jcs.02470 CrossRefPubMedGoogle Scholar
  69. Ramos JW (2008) The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells. Int J Biochem Cell Biol 40:2707–2719. doi: 10.1016/j.biocel.2008.04.009 CrossRefPubMedGoogle Scholar
  70. Rawlings JS, Rosler KM, Harrison DA (2004) The JAK/STAT signaling pathway. J Cell Sci 117:1281–1283. doi: 10.1242/jcs.00963 CrossRefPubMedGoogle Scholar
  71. Reusch HP, Zimmermann S, Schaefer M, Paul M, Moelling K (2001) Regulation of Raf by Akt controls growth and differentiation in vascular smooth muscle cells. J Biol Chem 276:33630–33637. doi: 10.1074/jbc.M105322200 CrossRefPubMedGoogle Scholar
  72. Risso G, Blaustein M, Pozzi B, Mammi P, Srebrow A (2015) Akt/PKB: one kinase, many modifications. Biochem J 468:203–214. doi: 10.1042/BJ20150041 CrossRefPubMedGoogle Scholar
  73. Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J (2007) RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 282:14056–14064. doi: 10.1074/jbc.M700906200 CrossRefPubMedPubMedCentralGoogle Scholar
  74. Royuela M, Arenas MI, Bethencourt FR, Sanchez-Chapado M, Fraile B, Paniagua R (2002) Regulation of proliferation/apoptosis equilibrium by mitogen-activated protein kinases in normal, hyperplastic, and carcinomatous human prostate. Hum Pathol 33:299–306CrossRefGoogle Scholar
  75. Scrima M, De Marco C, Fabiani F, Franco R, Pirozzi G, Rocco G, Ravo M, Weisz A, Zoppoli P, Ceccarelli M, Botti G, Malanga D, Viglietto G (2012) Signaling networks associated with AKT activation in non-small cell lung cancer (NSCLC): new insights on the role of phosphatydil-inositol-3 kinase. PLoS One 7:e30427. doi: 10.1371/journal.pone.0030427 CrossRefPubMedPubMedCentralGoogle Scholar
  76. Shahbazian D, Roux PP, Mieulet V, Cohen MS, Raught B, Taunton J, Hershey JW, Blenis J, Pende M, Sonenberg N (2006) The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. EMBO J 25:2781–2791. doi: 10.1038/sj.emboj.7601166 CrossRefPubMedPubMedCentralGoogle Scholar
  77. Shi H, Kong X, Ribas A, Lo RS (2011) Combinatorial treatments that overcome PDGFRbeta-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res 71:5067–5074. doi: 10.1158/0008-5472.CAN-11-0140 CrossRefPubMedPubMedCentralGoogle Scholar
  78. Shimamura A, Ballif BA, Richards SA, Blenis J (2000) Rsk1 mediates a MEK-MAP kinase cell survival signal. Curr Biol 10:127–135CrossRefGoogle Scholar
  79. Sirois J, Daudelin JF, Boulet S, Marquis M, Meloche S, Labrecque N (2015) The atypical MAPK ERK3 controls positive selection of thymocytes. Immunology 145:161–169. doi: 10.1111/imm.12433 CrossRefPubMedPubMedCentralGoogle Scholar
  80. Spoerke JM, O’Brien C, Huw L, Koeppen H, Fridlyand J, Brachmann RK, Haverty PM, Pandita A, Mohan S, Sampath D, Friedman LS, Ross L, Hampton GM, Amler LC, Shames DS, Lackner MR (2012) Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin Cancer Res 18:6771–6783. doi: 10.1158/1078-0432.CCR-12-2347 CrossRefPubMedGoogle Scholar
  81. Sun C, Bernards R (2014) Feedback and redundancy in receptor tyrosine kinase signaling: relevance to cancer therapies. Trends Biochem Sci 39:465–474. doi: 10.1016/j.tibs.2014.08.010 CrossRefPubMedGoogle Scholar
  82. Sun M, Paciga JE, Feldman RI, Yuan Z, Coppola D, Lu YY, Shelley SA, Nicosia SV, Cheng JQ (2001) Phosphatidylinositol-3-OH kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K. Cancer Res 61:5985–5991PubMedGoogle Scholar
  83. Surucu B, Bozulic L, Hynx D, Parcellier A, Hemmings BA (2008) In vivo analysis of protein kinase B (PKB)/Akt regulation in DNA-PKcs-null mice reveals a role for PKB/Akt in DNA damage response and tumorigenesis. J Biol Chem 283:30025–30033. doi: 10.1074/jbc.M803053200 CrossRefPubMedPubMedCentralGoogle Scholar
  84. Tang ED, Nunez G, Barr FG, Guan KL (1999) Negative regulation of the forkhead transcription factor FKHR by Akt. J Biol Chem 274:16741–16746CrossRefGoogle Scholar
  85. Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–241. doi: 10.1038/nrm2312 CrossRefPubMedGoogle Scholar
  86. van Gorp AG, van der Vos KE, Brenkman AB, Bremer A, van den Broek N, Zwartkruis F, Hershey JW, Burgering BM, Calkhoven CF, Coffer PJ (2009) AGC kinases regulate phosphorylation and activation of eukaryotic translation initiation factor 4B. Oncogene 28:95–106. doi: 10.1038/onc.2008.367 CrossRefPubMedGoogle Scholar
  87. Vansteenkiste JF, Canon JL, Braud FD, Grossi F, De Pas T, Gray JE, Su WC, Felip E, Yoshioka H, Gridelli C, Dy GK, Thongprasert S, Reck M, Aimone P, Vidam GA, Roussou P, Wang YA, Di Tomaso E, Soria JC (2015) Safety and efficacy of buparlisib (BKM120) in patients with PI3K pathway-activated non-small cell lung cancer: results from the phase II BASALT-1 study. J Thorac Oncol 10:1319–1327. doi: 10.1097/JTO.0000000000000607 CrossRefPubMedPubMedCentralGoogle Scholar
  88. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501. doi: 10.1038/nrc839 CrossRefPubMedGoogle Scholar
  89. Wada T, Penninger JM (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene 23:2838–2849. doi: 10.1038/sj.onc.1207556 CrossRefPubMedGoogle Scholar
  90. Waskiewicz AJ, Flynn A, Proud CG, Cooper JA (1997) Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J 16:1909–1920. doi: 10.1093/emboj/16.8.1909 CrossRefPubMedPubMedCentralGoogle Scholar
  91. Wicki A, Mandala M, Massi D, Taverna D, Tang H, Hemmings BA, Xue G (2016) Acquired resistance to clinical cancer therapy: a twist in physiological signaling. Physiol Rev 96:805–829. doi: 10.1152/physrev.00024.2015 CrossRefPubMedGoogle Scholar
  92. Widmann C, Gibson S, Jarpe MB, Johnson GL (1999) Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 79:143–180CrossRefGoogle Scholar
  93. Will M, Qin AC, Toy W, Yao Z, Rodrik-Outmezguine V, Schneider C, Huang X, Monian P, Jiang X, de Stanchina E, Baselga J, Liu N, Chandarlapaty S, Rosen N (2014) Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling. Cancer Discov 4:334–347. doi: 10.1158/2159-8290.CD-13-0611 CrossRefPubMedPubMedCentralGoogle Scholar
  94. Xie X, Zhang D, Zhao B, Lu MK, You M, Condorelli G, Wang CY, Guan KL (2011) IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A 108:6474–6479. doi: 10.1073/pnas.1016132108 CrossRefPubMedPubMedCentralGoogle Scholar
  95. Xue G, Restuccia DF, Lan Q, Hynx D, Dirnhofer S, Hess D, Ruegg C, Hemmings BA (2012) Akt/PKB-mediated phosphorylation of Twist1 promotes tumor metastasis via mediating cross-talk between PI3K/Akt and TGF-beta signaling axes. Cancer Discov 2:248–259. doi: 10.1158/2159-8290.CD-11-0270 CrossRefPubMedGoogle Scholar
  96. Yamnik RL, Holz MK (2010) mTOR/S6K1 and MAPK/RSK signaling pathways coordinately regulate estrogen receptor alpha serine 167 phosphorylation. FEBS Lett 584:124–128. doi: 10.1016/j.febslet.2009.11.041 CrossRefPubMedGoogle Scholar
  97. Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, Lang JY, Lai CC, Chang CJ, Huang WC, Huang H, Kuo HP, Lee DF, Li LY, Lien HC, Cheng X, Chang KJ, Hsiao CD, Tsai FJ, Tsai CH, Sahin AA, Muller WJ, Mills GB, Yu D, Hortobagyi GN, Hung MC (2008) ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 10:138–148. doi: 10.1038/ncb1676 CrossRefPubMedPubMedCentralGoogle Scholar
  98. Yang L, Hou Y, Yuan J, Tang S, Zhang H, Zhu Q, Du YE, Zhou M, Wen S, Xu L, Tang X, Cui X, Liu M (2015) Twist promotes reprogramming of glucose metabolism in breast cancer cells through PI3K/AKT and p53 signaling pathways. Oncotarget 6:25755–25769. doi: 10.18632/oncotarget.4697 CrossRefPubMedPubMedCentralGoogle Scholar
  99. Yu Y, Yoon SO, Poulogiannis G, Yang Q, Ma XM, Villen J, Kubica N, Hoffman GR, Cantley LC, Gygi SP, Blenis J (2011) Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332:1322–1326. doi: 10.1126/science.1199484 CrossRefPubMedPubMedCentralGoogle Scholar
  100. Zhang R, Luo D, Miao R, Bai L, Ge Q, Sessa WC, Min W (2005) Hsp90-Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis. Oncogene 24:3954–3963. doi: 10.1038/sj.onc.1208548 CrossRefPubMedGoogle Scholar
  101. Zheng Y, Peng M, Wang Z, Asara JM, Tyner AL (2010) Protein tyrosine kinase 6 directly phosphorylates AKT and promotes AKT activation in response to epidermal growth factor. Mol Cell Biol 30:4280–4292. doi: 10.1128/MCB.00024-10 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of PharmacologyZhejiang University, School of Basic Medical SciencesHangzhouChina
  2. 2.Department of BiomedicineUniversity Hospital BaselBaselSwitzerland

Personalised recommendations