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Demagny H, De Robertis EM. Point mutations in the tumor suppressor Smad4/DPC4 enhance its phosphorylation by GSK3 and reversibly inactivate TGF-β signaling. Mol Cell Oncol. 2015;3(1):e1025181doi: 10.1080/23723556.2015.1025181.
Demagny, H., & De Robertis, E. M. (2016). Point mutations in the tumor suppressor Smad4/DPC4 enhance its phosphorylation by GSK3 and reversibly inactivate TGF-β signaling. Molecular & cellular oncology, 3(1), e1025181. https://doi.org/10.1080/23723556.2015.1025181
Demagny, Hadrien, and De Robertis, Edward M. "Point mutations in the tumor suppressor Smad4/DPC4 enhance its phosphorylation by GSK3 and reversibly inactivate TGF-β signaling." Molecular & cellular oncology vol. 3,1 (2016): e1025181. doi: https://doi.org/10.1080/23723556.2015.1025181
Demagny H, De Robertis EM. Point mutations in the tumor suppressor Smad4/DPC4 enhance its phosphorylation by GSK3 and reversibly inactivate TGF-β signaling. Mol Cell Oncol. 2015 Apr 14;3(1):e1025181. doi: 10.1080/23723556.2015.1025181. eCollection 2016 Jan. PMID: 27308538; PMCID: PMC4845174.
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Mol Cell Oncol. 2015 Apr 14;3(1):e1025181. doi: 10.1080/23723556.2015.1025181. eCollection 2016 Jan.

Point mutations in the tumor suppressor Smad4/DPC4 enhance its phosphorylation by GSK3 and reversibly inactivate TGF-β signaling.

Molecular & cellular oncology

Hadrien Demagny, Edward M De Robertis

Affiliations

  1. Howard Hughes Medical Institute and Department of Biological Chemistry; University of California ; Los Angeles, CA USA.

PMID: 27308538 PMCID: PMC4845174 DOI: 10.1080/23723556.2015.1025181

Abstract

The tumor suppressor Smad4/DPC4 is an essential transcription factor in the TGF-β pathway and is frequently mutated or deleted in prostate, colorectal, and pancreatic carcinomas. We recently discovered that Smad4 activity and stability are regulated by the FGF/EGF and Wnt signaling pathways through a series of MAPK and GSK3 phosphorylation sites located in its linker region. In the present study, we report that loss-of-function associated with 2 point mutations commonly found in colorectal and pancreatic cancers results from enhanced Smad4 phosphorylation by GSK3, generating a phosphodegron that leads to subsequent β-TrCP-mediated polyubiquitination and proteasomal degradation. Using chemical GSK3 inhibitors, we show that Smad4 point mutant proteins can be stabilized and TGF-β signaling restored in cancer cells harboring such mutations.

Keywords: BMP; CDK; Caco-2; DPC4; GSK3; MAPK; Wnt/STOP; pancreatic cancer; prostate cancer; β-TrCP

References

  1. Oncogene. 1999 Jan 28;18(4):849-54 - PubMed
  2. Oncogene. 1999 Mar 25;18(12):2039-46 - PubMed
  3. Annu Rev Cell Dev Biol. 1999;15:435-67 - PubMed
  4. J Biol Chem. 2000 Jan 21;275(3):2115-22 - PubMed
  5. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4820-5 - PubMed
  6. EMBO J. 2000 Jun 1;19(11):2580-91 - PubMed
  7. Annu Rev Biochem. 2001;70:503-33 - PubMed
  8. Nat Rev Mol Cell Biol. 2001 Oct;2(10):769-76 - PubMed
  9. Clin Cancer Res. 2001 Dec;7(12):4115-21 - PubMed
  10. J Biol Chem. 2002 Jun 21;277(25):22111-4 - PubMed
  11. Mol Cell Biol. 2003 Jan;23(1):402-13 - PubMed
  12. Biochem J. 2004 Apr 1;379(Pt 1):209-16 - PubMed
  13. J Biol Chem. 2004 Apr 9;279(15):14484-7 - PubMed
  14. Nat Cell Biol. 2004 Oct;6(10):931-40 - PubMed
  15. J Natl Cancer Inst. 2005 Feb 2;97(3):166-7 - PubMed
  16. Am J Pathol. 2005 May;166(5):1379-92 - PubMed
  17. Cytokine Growth Factor Rev. 2006 Feb-Apr;17(1-2):41-58 - PubMed
  18. Future Oncol. 2006 Feb;2(1):91-100 - PubMed
  19. Science. 2007 Jun 15;316(5831):1619-22 - PubMed
  20. Cell. 2008 Jul 25;134(2):215-30 - PubMed
  21. Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5165-70 - PubMed
  22. Dev Cell. 2009 Jul;17(1):9-26 - PubMed
  23. Cell. 2009 Nov 13;139(4):757-69 - PubMed
  24. J Biol Chem. 2010 Nov 26;285(48):37159-69 - PubMed
  25. Cell. 2010 Dec 23;143(7):1136-48 - PubMed
  26. Nature. 2011 Feb 10;470(7333):269-73 - PubMed
  27. Cell. 2011 Mar 4;144(5):646-74 - PubMed
  28. Genes Dev. 2011 Jun 15;25(12):1275-88 - PubMed
  29. Front Mol Neurosci. 2011 Oct 31;4:32 - PubMed
  30. Cell. 2012 Jun 8;149(6):1192-205 - PubMed
  31. Nat Rev Mol Cell Biol. 2012 Oct;13(10):616-30 - PubMed
  32. Cell. 2012 Dec 21;151(7):1443-56 - PubMed
  33. Science. 2013 Mar 29;339(6127):1546-58 - PubMed
  34. Mol Cell. 2014 Feb 6;53(3):444-57 - PubMed
  35. Mol Cell. 2014 May 22;54(4):663-74 - PubMed
  36. Cell Rep. 2014 Oct 23;9(2):688-700 - PubMed
  37. Mol Cell Oncol. 2015 Jan 30;3(2):e989133 - PubMed
  38. Science. 1996 Jan 19;271(5247):350-3 - PubMed
  39. Cancer Res. 1996 Jun 1;56(11):2527-30 - PubMed
  40. Oncogene. 1997 Apr 24;14(16):1891-9 - PubMed
  41. EMBO J. 1998 Jun 1;17(11):3091-100 - PubMed
  42. Annu Rev Biochem. 1998;67:753-91 - PubMed

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