Skip to main content
SpringerLink
Log in

Ski, SnoN, and Akt as Negative Regulators of Smad Activity: Balancing Cell Death and Cell Survival

  • Chapter
Transforming Growth Factor-β in Cancer Therapy, Volume I

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 1603 Accesses

Abstract

Cytokines of the transforming growth factor-β (TGF-β) superfamily exert many of their diverse effects via the recruitment of the Smad proteins to activate transcription of TGF-β target genes. Activities of the Smad proteins have been shown to be regulated through interaction with cellular partners. Among these, the protooncogenes of the Ski family, Ski, and SnoN, and the protein kinase Akt can negatively modulate the Smad signaling via differents mechanisms to affect various downstream TGF-β responses. Here, we review how Ski, SnoN, and Akt act as repressors of Smad activity to antagonizes TGF-β signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Roberts AB, Flanders KC, Heine UI, et al. Transforming growth factor-beta: multifunctional regulator of differentiation and development. Philos Trans R Soc Lond B Biol Sci 1990;327:145–154.

    Article  CAS  PubMed  Google Scholar 

  2. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 2001;29:117–129.

    Article  CAS  PubMed  Google Scholar 

  3. Moses HL, Yang EY, Pietenpol JA. TGF-beta stimulation and inhibition of cell proliferation: new mechanistic insights. Cell 1990;63:245–247.

    Article  CAS  PubMed  Google Scholar 

  4. Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med 2000;342:1350–1358.

    Article  CAS  PubMed  Google Scholar 

  5. Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 2000;103:295–309.

    Article  PubMed  Google Scholar 

  6. ten Dijke P, Hill CS. New insights into TGF-beta-Smad signalling. Trends Biochem Sci 2004;29:265–273.

    Article  PubMed  CAS  Google Scholar 

  7. Heldin C-H, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 1997;390:465–471.

    Article  CAS  PubMed  Google Scholar 

  8. Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003; 113:685–700.

    Article  CAS  PubMed  Google Scholar 

  9. Attisano L, Wrana JL. Smads as transcriptional co-modulators. Curr Opin Cell Biol 2000;12:235–243.

    Article  CAS  PubMed  Google Scholar 

  10. Miyazono K, ten Dijke P, Heldin C-H. TGF-beta signaling by Smad proteins. Adv Immunol 2000;75:115–157.

    Article  CAS  PubMed  Google Scholar 

  11. Massagué J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. EMBO J 2000;19:1745–1754.

    Article  PubMed  Google Scholar 

  12. Zhang Y, Derynck R. Regulation of Smad signalling by protein associations and signalling crosstalk. Trends Cell Biol 1999;9:274–279.

    Article  CAS  PubMed  Google Scholar 

  13. Li Y, Turck CM, Teumer JK, Stavnezer E. Unique sequence, ski, in Sloan-Kettering avian retroviruses with properties of a new cell-derived oncogene. J Virol 1986;57:1065–1072.

    CAS  PubMed  Google Scholar 

  14. Nomura N, Sasamoto S, Ishii S, Date T, Matsui M, Ishizaki R. Isolation of human cDNA clones of ski and the ski-related gene, sno. Nucleic Acids Res 1989;17:5489–5500.

    Article  CAS  PubMed  Google Scholar 

  15. Pearson-White S, Crittenden R. Proto-oncogene Sno expression, alternative isoforms and immediate early serum response. Nucleic Acids Res 1997;25:2930–2937.

    Article  CAS  PubMed  Google Scholar 

  16. Liu X, Sun Y, Weinberg RA, Lodish HF. Ski/Sno and TGF-beta signaling. Cytokine Growth Factor Rev 2001;12:1–8.

    Article  CAS  PubMed  Google Scholar 

  17. Luo K. Ski and SnoN: negative regulators of TGF-beta signaling. Curr Opin Genet Dev 2004;14:65–70.

    Article  CAS  PubMed  Google Scholar 

  18. Heyman HC, Stavnezer E. A carboxyl-terminal region of the ski oncoprotein mediates homodimerization as well as heterodimerization with the related protein SnoN. J Biol Chem 1994;269:26,996–27,003.

    CAS  PubMed  Google Scholar 

  19. Nagase T, Nomura N, Ishii S. Complex formation between proteins encoded by the ski gene family. J Biol Chem 1993;268:13,710–13,716.

    CAS  PubMed  Google Scholar 

  20. Cohen SB, Zheng G, Heyman HC, Stavnezer E. Heterodimers of the SnoN and Ski oncoproteins form preferentially over homodimers and are more potent transforming agents. Nucleic Acids Res 1999;27:1006–1014.

    Article  CAS  PubMed  Google Scholar 

  21. Colmenares C, Stavnezer E. The ski oncogene induces muscle differentiation in quail embryo cells. Cell 1989;59:293–303.

    Article  CAS  PubMed  Google Scholar 

  22. Lyons GE, Micales BK, Herr MJ, et al. Protooncogene c-ski is expressed in both proliferating and postmitotic neuronal populations. Dev Dyn 1994;201:354–365.

    CAS  PubMed  Google Scholar 

  23. Namciu S, Lyons GE, Micales BK, Heyman HC, Colmenares C, Stavnezer E. Enhanced expression of mouse c-ski accompanies terminal skeletal muscle differentiation in vivo and in vitro. Dev Dyn 1995;204:291–300.

    CAS  PubMed  Google Scholar 

  24. Wang W, Mariani FV, Harland RM, Luo K. Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells. Proc Natl Acad Sci USA 2000;97:14,394–14,399.

    Article  CAS  PubMed  Google Scholar 

  25. Amaravadi LS, Neff AW, Sleeman JP, Smith RC. Autonomous neural axis formation by ectopic expression of the protooncogene c-ski. Dev Biol 1997;192:392–404.

    Article  CAS  PubMed  Google Scholar 

  26. Kaufman CD, martinez-Rodriguez G, Hackett PB, Jr. Ectopic expression of c-ski disrupts gastrulation and neural patterning in zebrafish. Mech Dev 2000;95:147–162.

    Article  CAS  PubMed  Google Scholar 

  27. Sutrave P, Kelly AM, Hughes SH. Ski can cause selective growth of skeletal muscle in transgenic mice. Genes Dev 1990;4:1462–1472.

    Article  CAS  PubMed  Google Scholar 

  28. Berk M, Desai SY, Heyman HC, Colmenares C. Mice lacking the ski proto-oncogene have defects in neurulation, craniofacial, patterning, and skeletal muscle development. Genes Dev 1997;11:2029–2039.

    Article  CAS  PubMed  Google Scholar 

  29. Colmenares C, Heilstedt HA, Shaffer LG, et al. Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski−/− mice. Nat Genet 2002;30:106–109.

    Article  CAS  PubMed  Google Scholar 

  30. Pearson-White S. SnoI, a novel alternatively spliced isoform of the ski protooncogene homolog, sno. Nucleic Acids Res 1993;21:4632–4638.

    Article  CAS  PubMed  Google Scholar 

  31. Boyer PL, Colmenares C, Stavnezer E, Hughes SH. Sequence and biological activity of chicken snoN cDNA clones. Oncogene 1993;8:457–466.

    CAS  PubMed  Google Scholar 

  32. Pearson-White S, McDuffie M. Defective T-cell activation is associated with augmented transforming growth factor Beta sensitivity in mice with mutations in the Sno gene. Mol Cell Biol 2003;23:5446–5459.

    Article  CAS  PubMed  Google Scholar 

  33. Shinagawa T, Dong HD, Xu M, Maekawa T, Ishii S. The sno gene, which encodes a component of the histone deacetylase complex, acts as a tumor suppressor in mice. EMBO J 2000;19:2280–2291.

    Article  CAS  PubMed  Google Scholar 

  34. Arndt S, Poser I, Schubert T, Moser M, Bosserhoff AK. Cloning and functional characterization of a new Ski homolog, Fussel-18, specifically expressed in neuronal tissues. Lab Invest 2005;85:1330–1341.

    Article  CAS  PubMed  Google Scholar 

  35. Mizuhara E, Nakatani T, Minaki Y, Sakamoto Y, Ono Y. Corl1, a novel neuronal lineage-specific transcriptional corepressor for the homeodomain transcription factor Lbx1. J Biol Chem 2005;280:3645–3655.

    Article  CAS  PubMed  Google Scholar 

  36. Xu W, Angelis K, Danielpour D, et al. Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor. Proc Natl Acad Sci USA 2000;97:5924–5929.

    Article  CAS  PubMed  Google Scholar 

  37. Sun Y, Liu X, Eaton EN, Lane WS, Lodish HF, Weinberg RA. Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling. Mol Cell 1999;4:499–509.

    Article  CAS  PubMed  Google Scholar 

  38. Stroschein SL, Wang W, Zhou S, Zhou Q, Luo K. Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science 1999;286:771–774.

    Article  CAS  PubMed  Google Scholar 

  39. Luo K; Stroschein SL, Wang W, et al. The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev 1999;13:2196–2206.

    Article  CAS  PubMed  Google Scholar 

  40. Akiyoshi S, Inoue H, Hanai J, et al. c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads. J Biol Chem 1999;274:35,269–35,277.

    Article  CAS  PubMed  Google Scholar 

  41. He J, Tegen SB, Krawitz AR, Martin GS, Luo K. The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins. J Biol Chem 2003;278:30,540–30,547.

    Article  CAS  PubMed  Google Scholar 

  42. Tokitou F, Nomura T, Khan MM, et al. Viral ski inhibits retinoblastoma protein (Rb)-mediated transcriptional repression in a dominant negative fashion. J Biol Chem 1999;274:4485–4488.

    Article  CAS  PubMed  Google Scholar 

  43. Nomura T, Khan MM, Kaul SC, et al. Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor. Genes Dev 1999;13:412–423.

    Article  CAS  PubMed  Google Scholar 

  44. Kokura K, Kaul SC, Wadhwa R, et al. The Ski protein family is required for MeCP2-mediated transcriptional repression. J Biol Chem 2001;276:34,115–34,121.

    Article  CAS  PubMed  Google Scholar 

  45. Harada J, Kokura K, Kanei-Ishii C, et al. Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation. J Biol Chem 2003;278:38,998–39,005.

    Article  CAS  PubMed  Google Scholar 

  46. Wu JW, Krawitz AR, Chai J, et al. Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: insights on Ski-mediated repression of TGF-beta signaling. Cell 2002;111:357–367.

    Article  CAS  PubMed  Google Scholar 

  47. Takeda M, Mizuide M, Oka M, et al. Interaction with Smad4 is indispensable for suppression of BMP signaling by c-Ski. Mol Biol Cell 2004;15:963–972.

    Article  CAS  PubMed  Google Scholar 

  48. Pessah M, Marais J, Prunier C, et al. c-Jun associates with the oncoprotein Ski and suppresses Smad2 transcriptional activity. J Biol Chem 2002;277:29,094–29,100.

    Article  CAS  PubMed  Google Scholar 

  49. Pessah M, Prunier C, Marais J, et al. c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity. Proc Natl Acad Sci USA 2001;98:6198–6203.

    Article  CAS  PubMed  Google Scholar 

  50. Wilson JJ, Malakhova M, Zhang R, Joachimiak A, Hegde RS. Crystal structure of the dachshund homology domain of human SKI. Structure (Camb) 2004;12:785–792.

    Article  CAS  Google Scholar 

  51. Dahl R, Wani B, Hayman MJ. The Ski oncoprotein interacts with Skip, the human homolog of Drosophila Bx42. Oncogene 1998;16:1579–1586.

    Article  CAS  PubMed  Google Scholar 

  52. Prathapam T, Kuhne C, Hayman M, Banks L. Ski interacts with the evolutionarily conserved SNW domain of Skip. Nucleic Acids Res 2001;29:3469–3476.

    Article  CAS  PubMed  Google Scholar 

  53. Khan MM, Nomura T, Kim H, et al. Role of PML and PML-RARalpha in Mad-mediated transcriptional repression. Mol Cell 2001;7:1233–1243.

    Article  CAS  PubMed  Google Scholar 

  54. Dahl R, Kieslinger M, Beug H, Hayman MJ. Transformation of hematopoietic cells by the Ski oncoprotein involves repression of retinoic acid receptor signaling. Proc Natl Acad Sci USA 1998;95:11,187–11,192.

    Article  CAS  PubMed  Google Scholar 

  55. Medrano EE. Repression of TGF-beta signaling by the oncogenic protein SKI in human melanomas: consequences for proliferation, survival, and metastasis. Oncogene 2003;22:3123–3129.

    CAS  PubMed  Google Scholar 

  56. Kokura K, Kim H, Shinagawa T, Khan MM, Nomura T, Ishii S. The Ski-binding protein C184M negatively regulates tumor growth factor-beta signaling by sequestering the Smad proteins in the cytoplasm. J Biol Chem 2003;278:20,133–20,139.

    Article  CAS  PubMed  Google Scholar 

  57. Dai P, Shinagawa T, Nomura T, et al. Ski is involved in transcriptional regulation by the repressor and full-length forms of Gli3. Genes Dev 2002;16:2843–2848.

    Article  CAS  PubMed  Google Scholar 

  58. Zhang F, Lundin M, Ristimaki A, et al. Ski-related novel protein N (SnoN), a negative controller of transforming growth factor-beta signaling, is a prognostic marker in estrogen receptor-positive breast carcinomas. Cancer Res 2003;63:5005–5010.

    CAS  PubMed  Google Scholar 

  59. Reed JA, Bales E, Xu W, Okan NA, Bandyopadhyay D, Medrano EE. Cytoplasmic localization of the oncogenic protein Ski in human cutaneous melanomas in vivo: functional implications for transforming growth factor beta signaling. Cancer Res 2001;61:8074–8078.

    CAS  PubMed  Google Scholar 

  60. Imoto I, Pimkhaokham A, Fukuda Y, et al. SNO is a probable target for gene amplification at 3q26 in squamous-cell carcinomas of the esophagus. Biochem Biophys Res Commun 2001;286:559–565.

    Article  CAS  PubMed  Google Scholar 

  61. Fumagalli S, Doneda L, Nomura N, Larizza L. Expression of the c-ski proto-oncogene in human melanoma cell lines. Melanoma Res 1993;3:23–27.

    Article  CAS  PubMed  Google Scholar 

  62. Wan Y, Liu X, Kirschner MW. The anaphase-promoting complex mediates TGF-beta signaling by targeting SnoN for destruction. Mol Cell 2001;8:1027–1039.

    Article  CAS  PubMed  Google Scholar 

  63. Bonni S, Wang HR, Causing CG, et al. TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nat Cell Biol 2001;3:587–595.

    Article  CAS  PubMed  Google Scholar 

  64. Stroschein SL, Bonni S, Wrana JL, Luo K. Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN. Genes Dev 2001;15:2822–2836.

    CAS  PubMed  Google Scholar 

  65. Zhu Q, Pearson-White S, Luo K. Requirement for the SnoN oncoprotein in transforming growth factor beta-induced oncogenic transformation of fibroblast cells. Mol Cell Biol 2005;25:10,731–10,744.

    Article  CAS  PubMed  Google Scholar 

  66. Edmiston JS, Yeudall WA, Chung TD, Lebman DA. Inability of transforming growth factor-beta to cause SnoN degradation leads to resistance to transforming growth factor-beta-induced growth arrest in esophageal cancer cells. Cancer Res 2005;65:4782–4788.

    Article  CAS  PubMed  Google Scholar 

  67. Krakowski AR, Laboureau J, Mauviel A, Bissell MJ, Luo K. Cytoplasmic SnoN in normal tissues and nonmalignant cells antagonizes TGF-beta signaling by sequestration of the Smad proteins. Proc Natl Acad Sci USA 2005;102:12,437–12,442.

    Article  CAS  PubMed  Google Scholar 

  68. Marcelain K, Hayman MJ. The Ski oncoprotein is upregulated and localized at the centrosomes and mitotic spindle during mitosis. Oncogene 2005;24:4321–4329.

    Article  CAS  PubMed  Google Scholar 

  69. Sutrave P, Copeland TD, Showalter SD, Hughes SH. Characterization of chicken c-ski oncogene products expressed by retrovirus vectors. Mol Cell Biol 1990;10:3137–3144.

    CAS  PubMed  Google Scholar 

  70. Macdonald M, Wan Y, Wang W, et al. Control of cell cycle-dependent degradation of c-Ski proto-oncoprotein by Cdc34. Oncogene 2004;23:5643–5653.

    Article  CAS  PubMed  Google Scholar 

  71. Fukuchi M, Nakajima M, Fukai Y, et al. Increased expression of c-Ski as a co-repressor in transforming growth factor-beta signaling correlates with progression of esophageal squamous cell carcinoma. Int J Cancer 2004;108:818–824.

    Article  CAS  PubMed  Google Scholar 

  72. Buess M, Terracciano L, Reuter J, et al. Amplification of SKI is a prognostic marker in early colorectal cancer. Neoplasia 2004;6:207–212.

    Article  CAS  PubMed  Google Scholar 

  73. Shinagawa T, Nomura T, Colmenares C, Ohira M, Nakagawara A, Ishii S. Increased susceptibility to tumorigenesis of ski-deficient heterozygous mice. Oncogene 2001;20:8100–8108.

    Article  CAS  PubMed  Google Scholar 

  74. Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer 2003;3:203–216.

    Article  CAS  PubMed  Google Scholar 

  75. Smedley D, Sidhar S, Birdsall S, et al. Characterization of chromosome 1 abnormalities in malignant melanomas. Genes Chromosomes Cancer 2000;28:121–125.

    Article  CAS  PubMed  Google Scholar 

  76. Poser I, Rothhammer T, Dooley S, Weiskirchen R, Bosserhoff AK. Characterization of Sno expression in malignant melanoma. Int J Oncol 2005;26:1411–1417.

    CAS  PubMed  Google Scholar 

  77. Levy L, Hill CS. Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev 2005.

    Google Scholar 

  78. Bhowmick NA, Ghiassi M, Bakin A, et al. Transforming growth factor-betal mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 2001;12:27–36.

    CAS  PubMed  Google Scholar 

  79. Moustakas A, Heldin C-H. Non-Smad TGF-beta signals. J Cell Sci 2005;118:3573–3584.

    Article  CAS  PubMed  Google Scholar 

  80. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425:577–584.

    Article  CAS  PubMed  Google Scholar 

  81. Shin I, Bakin AV, Rodeck U, Brunet A, Arteaga CL. Transforming growth factor beta enhances epithelial cell survival via Akt-dependent regulation of FKHRL1. Mol Biol Cell 2001;12:3328–3339.

    CAS  PubMed  Google Scholar 

  82. Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem 2000;275:36,803–36,810.

    Article  CAS  PubMed  Google Scholar 

  83. Brazil DP, Hemmings BA. Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 2001;26:657–664.

    Article  CAS  PubMed  Google Scholar 

  84. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999;13:2905–2927.

    Article  CAS  PubMed  Google Scholar 

  85. Yang ZZ, Tschopp O, Baudry A, Dummler B, Hynx D, Hemmings BA. Physiological functions of protein kinase B/Akt. Biochem Soc Trans 2004;32:350–354.

    Article  CAS  PubMed  Google Scholar 

  86. Bellacosa A, Franke TF, Gonzalez-Portal ME, et al. Structure, expression and chromosomal mapping of c-akt: relationship to v-akt and its implications. Oncogene 1993;8:745–754.

    CAS  PubMed  Google Scholar 

  87. Altomare DA, Lyons GE, Mitsuuchi Y, Cheng JQ, Testa JR. Akt2 mRNA is highly expressed in embryonic brown fat and the AKT2 kinase is activated by insulin. Oncogene 1998;16:2407–2411.

    Article  CAS  PubMed  Google Scholar 

  88. Altomare DA, Guo K, Cheng JQ, Sonoda G, Walsh K, Testa JR. Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene. Oncogene 1995;11:1055–1160.

    CAS  PubMed  Google Scholar 

  89. Brodbeck D, Cron P, Hemmings BA. A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. J Biol Chem 1999;274:9133–9136.

    Article  CAS  PubMed  Google Scholar 

  90. Nakatani K, Sakaue H, Thompson DA, Weigel RJ, Roth RA. Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site. Biochem Biophys Res Commun 1999;257:906–910.

    Article  CAS  PubMed  Google Scholar 

  91. Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 2002;14:381–395.

    Article  CAS  PubMed  Google Scholar 

  92. Galetic I, Andjelkovic M, Meier R, Brodbeck D, Park J, Hemmings BA. Mechanism of protein kinase B activation by insulin/insulin-like growth factor-1 revealed by specific inhibitors of phosphoinositide 3-kinase-significance for diabetes and cancer. Pharmacol Ther 1999;82:409–425.

    Article  CAS  PubMed  Google Scholar 

  93. Currie RA, Walker KS, Gray A, et al. Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. Biochem J 1999;337 (Pt 3):575–583.

    Article  CAS  PubMed  Google Scholar 

  94. Sable CL, Filippa N, Filloux C, Hemmings BA, Van Obberghen E. Involvement of the pleckstrin homology domain in the insulin-stimulated activation of protein kinase B. J Biol Chem 1998;273:29,600–29,606.

    Article  CAS  PubMed  Google Scholar 

  95. Zhang X, Vik TA. Growth factor stimulation of hematopoietic cells leads to membrane translocation of AKT1 protein kinase. Leuk Res 1997;21:849–856.

    Article  CAS  PubMed  Google Scholar 

  96. Wijkander J, Holst LS, Rahn T, et al. Regulation of protein kinase B in rat adipocytes by insulin, vanadate, and peroxovanadate. Membrane translocation in response to peroxovanadate. J Biol Chem 1997;272:21,520–21,526.

    Article  CAS  PubMed  Google Scholar 

  97. Meier R, Alessi DR, Cron P, Andjelkovic M, Hemmings BA. Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta. J Biol Chem 1997;272:30,491–30,497.

    Article  CAS  PubMed  Google Scholar 

  98. Andjelkovic M, Alessi DR, Meier R, et al. Role of translocation in the activation and function of protein kinase B. J Biol Chem 1997;272:31,515–31,524.

    Article  CAS  PubMed  Google Scholar 

  99. Klippel A, Kavanaugh WM, Pot D, Williams LT. A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mol Cell Biol 1997;17:338–344.

    CAS  PubMed  Google Scholar 

  100. Frech M, Andjelkovic M, Ingley E, Reddy KK, Falck JR, Hemmings BA. High affinity binding of inositol phosphates and phosphoinositides to the pleckstrin homology domain of RAC/protein kinase B and their influence on kinase activity. J Biol Chem 1997;272:8474–8481.

    Article  CAS  PubMed  Google Scholar 

  101. Franke TF, Kaplan DR, Cantley LC, Toker A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science 1997;275:665–668.

    Article  CAS  PubMed  Google Scholar 

  102. James SR, Downes CP, Gigg R, Grove SJ, Holmes AB, Alessi DR. Specific binding of the Akt-1 protein kinase to phosphatidylinositol 3,4,5-trisphosphate without subsequent activation. Biochem J 1996; 315(Pt 3):709–713.

    CAS  PubMed  Google Scholar 

  103. Datta K, Bellacosa A, Chan TO, Tsichlis PN. Akt is a direct target of the phosphatidylinositol 3-kinase. Activation by growth factors, v-src and v-Ha-ras, in Sf9 and mammalian cells. J Biol Chem 1996;271:30,835–30,839.

    Article  CAS  PubMed  Google Scholar 

  104. Alessi DR, Deak M, Casamayor A, et al. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol 1997;7:776–789.

    Article  CAS  PubMed  Google Scholar 

  105. Balendran A, Casamayor A, Deak M, et al. PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. Curr Biol 1999;9:393–404.

    Article  CAS  PubMed  Google Scholar 

  106. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA 1998;95:11,211–11,216.

    Article  CAS  PubMed  Google Scholar 

  107. Persad S, Attwell S, Gray V, et al. Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343. J Biol Chem 2001;276:27,462–27,469.

    Article  CAS  PubMed  Google Scholar 

  108. Laine J, Kunstle G, Obata T, Sha M, Noguchi M. The protooncogene TCL1 is an Akt kinase coactivator. Mol Cell 2000;6:395–407.

    Article  CAS  PubMed  Google Scholar 

  109. Toker A, Newton AC. Akt/protein kinase B is regulated by autophosphorylation at the hypothetical PDK-2 site. J Biol Chem 2000;275:8271–8274.

    Article  CAS  PubMed  Google Scholar 

  110. Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005;9:59–71.

    Article  CAS  PubMed  Google Scholar 

  111. Hong F, Nguyen VA, Shen X, Kunos G, Gao B. Rapid activation of protein kinase B/Akt has a key role in antiapoptotic signaling during liver regeneration. Biochem Biophys Res Commun 2000;279:974–979.

    Article  CAS  PubMed  Google Scholar 

  112. Chen RH, Su YH, Chuang RL, Chang TY. Suppression of transforming growth factor-beta-induced apoptosis through a phosphatidylinositol 3-kinase/Akt-dependent pathway. Oncogene 1998;17:1959–1968.

    Article  CAS  PubMed  Google Scholar 

  113. Tanaka S, Wands JR. Insulin receptor substrate 1 overexpression in human hepatocellular carcinoma cells prevents transforming growth factor beta1-induced apoptosis. Cancer Res 1996;56:3391–3394.

    CAS  PubMed  Google Scholar 

  114. Remy I, Montmarquette A, Michnick SW: PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat Cell Biol 2004;6:358–365.

    Article  CAS  PubMed  Google Scholar 

  115. Conery AR, Cao Y, Thompson EA, Townsend CM, Jr., Ko TC, Luo K. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 2004;6:366–372.

    Article  CAS  PubMed  Google Scholar 

  116. Song K, Cornelius SC, Reiss M, Danielpour D. Insulin-like growth factor-I inhibits transcriptional responses of transforming growth factor-beta by phosphatidylinositol 3-kinase/Akt-dependent suppression of the activation of Smad3 but not Smad2. J Biol Chem 2003;278:38,342–38,351.

    Article  CAS  PubMed  Google Scholar 

  117. Danielpour D, Song K. Cross-talk between IGF-I and TGF-beta signaling pathways. Cytokine Growth Factor Rev 2006;17(1–2):59–74.

    Article  CAS  PubMed  Google Scholar 

  118. Tran H, Brunet A, Grenier JM, et al. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 2002;296:530–534.

    Article  CAS  PubMed  Google Scholar 

  119. Nakae J, Kitamura T, Silver DL, Accili D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J Clin Invest 2001;108:1359–167.

    CAS  PubMed  Google Scholar 

  120. Medema RH, Kops GJ, Bos JL, Burgering BM. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 2000;404:782–787.

    Article  CAS  PubMed  Google Scholar 

  121. Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 2001;21:952–965.

    Article  CAS  PubMed  Google Scholar 

  122. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857–868.

    Article  CAS  PubMed  Google Scholar 

  123. Seoane J, Le HV, Shen L, Anderson SA, Massagué J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 2004;117:211–223.

    Article  CAS  PubMed  Google Scholar 

  124. Zhu Q, Krakowski AR, Dunham EE, et al. Dual role of SnoN in mammalian tumorigenesis. Mol Cell Biol 2007;27(1):324–339.

    Article  CAS  PubMed  Google Scholar 

  125. Wrighton KH, Liang M, Bryan B, et al. TGF-β independent regulation of myogenesis by SnoN sumoylation. J Biol Chem 2007;282:6517–6524.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA

    Erwan Le Scolan PhD & Kunxin Luo PhD

Authors
  1. Erwan Le Scolan PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kunxin Luo PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press

About this chapter

Cite this chapter

Le Scolan, E., Luo, K. (2008). Ski, SnoN, and Akt as Negative Regulators of Smad Activity: Balancing Cell Death and Cell Survival. In: Transforming Growth Factor-β in Cancer Therapy, Volume I. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-292-2_9

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-292-2_9

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-714-3

  • Online ISBN: 978-1-59745-292-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation