Direct binding of MEK1 and MEK2 to AKT induces Foxo1 phosphorylation, cellular migration and metastasis.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Cell Movement* ; Protein Processing, Post-Translational*; Forkhead Box Protein O1/*metabolism ; MAP Kinase Kinase 1/*metabolism ; MAP Kinase Kinase 2/*metabolism ; Proto-Oncogene Proteins c-akt/*metabolism; Animals ; COS Cells ; Chlorocebus aethiops ; HeLa Cells ; Humans ; Neoplasm Metastasis ; Phosphorylation ; Protein Binding

Crosstalk between the ERK cascade and other signaling pathways is one of the means by which it acquires its signaling specificity. Here we identified a direct interaction of both MEK1 and MEK2 with AKT. The interaction is mediated by the proline rich domain of MEK1/2 and regulated by phosphorylation of Ser298 in MEK1, or Ser306 in MEK2, which we identified here as a novel regulatory site. We further developed a blocking peptide, which inhibits the interaction between MEK and AKT, and when applied to cells, affects migration and adhesion, but not proliferation. The specific mechanism of action of the MEK-AKT complex involves phosphorylation of the migration-related transcription factor FoxO1. Importantly, prevention of the interaction results in a decreased metastasis formation in a breast cancer mouse model. Thus, the identified interaction both sheds light on how signaling specificity is determined, and represents a possible new therapeutic target for metastatic cancer.

Biochim Biophys Acta. 2011 Sep;1813(9):1619-33. (PMID: 21167873)
J Cell Sci. 2003 Apr 1;116(Pt 7):1175-86. (PMID: 12615961)
Mol Cell. 2005 Apr 29;18(3):295-306. (PMID: 15866172)
Growth Factors. 2006 Mar;24(1):21-44. (PMID: 16393692)
Genes Cancer. 2011 Mar;2(3):195-209. (PMID: 21779493)
Science. 1999 Nov 26;286(5445):1741-4. (PMID: 10576742)
Cancer Res. 2012 Jan 1;72(1):210-9. (PMID: 22084396)
J Biol Chem. 2011 May 27;286(21):18903-13. (PMID: 21454680)
Nature. 2006 May 25;441(7092):424-30. (PMID: 16724053)
Mol Cell Biol. 1999 Jun;19(6):4279-88. (PMID: 10330169)
J Biol Chem. 2000 Sep 1;275(35):27354-9. (PMID: 10869359)
Biochim Biophys Acta. 2007 Aug;1773(8):1213-26. (PMID: 17112607)
Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18351-6. (PMID: 19805051)
Curr Opin Genet Dev. 2010 Feb;20(1):87-90. (PMID: 20006486)
Science. 1998 Sep 11;281(5383):1668-71. (PMID: 9733512)
J Clin Oncol. 2010 Feb 20;28(6):1075-83. (PMID: 20085938)
Pharmacol Res. 2012 Aug;66(2):105-43. (PMID: 22569528)
Oncogene. 2002 Feb 14;21(8):1299-303. (PMID: 11850850)
Oncogene. 2007 May 14;26(22):3291-310. (PMID: 17496923)
Adv Enzyme Regul. 2006;46:249-79. (PMID: 16854453)
Cancer Res. 2011 May 1;71(9):3257-67. (PMID: 21505104)
Trends Biochem Sci. 2011 Jun;36(6):320-8. (PMID: 21531565)
Nature. 1998 Nov 12;396(6707):180-3. (PMID: 9823899)
Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1473-80. (PMID: 16645158)
Curr Biol. 1994 Sep 1;4(9):798-806. (PMID: 7820549)
Nat Rev Cancer. 2009 Aug;9(8):550-62. (PMID: 19629070)
Mol Cell. 2008 Sep 26;31(6):850-61. (PMID: 18760948)
EMBO J. 1997 Nov 3;16(21):6426-38. (PMID: 9351825)
Sci STKE. 2003 Mar 04;2003(172):RE5. (PMID: 12621150)
J Biol Chem. 2002 Jan 4;277(1):528-34. (PMID: 11684694)
Mol Biol Cell. 2002 Jul;13(7):2276-88. (PMID: 12134068)
Methods Mol Biol. 2010;661:3-38. (PMID: 20811974)
J Biol Chem. 1998 Apr 24;273(17 ):10475-84. (PMID: 9553107)
Mol Cell. 2001 Aug;8(2):291-301. (PMID: 11545732)
Int J Cancer. 2009 Nov 15;125(10 ):2332-41. (PMID: 19637312)
Nat Med. 2008 Dec;14(12):1351-6. (PMID: 19029981)
Nat Struct Mol Biol. 2009 Mar;16(3):294-303. (PMID: 19219045)
Mol Cell. 2013 Apr 11;50(1):43-55. (PMID: 23453810)
Nature. 1994 Aug 18;370(6490):527-32. (PMID: 8052307)
Cancer Res. 2009 Jan 15;69(2):565-72. (PMID: 19147570)
J Cell Biol. 2003 Jul 21;162(2):281-91. (PMID: 12876277)
Oncogene. 2009 Jun 25;28(25):2365-9. (PMID: 19421139)
Mol Cell Biol. 2014 Jan;34(2):259-70. (PMID: 24216760)
Biochim Biophys Acta. 2004 Mar 11;1697(1-2):3-16. (PMID: 15023346)
Mol Cell Biol. 2007 Feb;27(3):803-17. (PMID: 17101779)
J Clin Invest. 2008 Sep;118(9):3065-74. (PMID: 18725988)
EMBO J. 1994 Apr 1;13(7):1610-9. (PMID: 8157000)
Biochim Biophys Acta. 2011 Nov;1813(11):1938-45. (PMID: 21708191)
Oncogene. 2008 Oct 27;27(50):6473-88. (PMID: 18955974)
Nat Rev Mol Cell Biol. 2012 Feb 23;13(3):195-203. (PMID: 22358332)
Cancer Res. 2006 Aug 15;66(16):8037-41. (PMID: 16912179)
Cell. 2007 Jun 29;129(7):1261-74. (PMID: 17604717)
Science. 1995 Apr 7;268(5207):100-2. (PMID: 7701328)
Science. 1999 Nov 26;286(5445):1738-41. (PMID: 10576741)
Nat Rev Cancer. 2011 Apr;11(4):289-301. (PMID: 21430697)
Biochem Biophys Res Commun. 2012 Jan 6;417(1):5-10. (PMID: 22177953)
J Biol Chem. 1994 Jul 22;269(29):19067-73. (PMID: 8034665)
Nature. 1999 Sep 2;401(6748):86-90. (PMID: 10485711)
Nat Cell Biol. 2008 Feb;10 (2):138-48. (PMID: 18204439)
Nat Commun. 2015 Mar 30;6:6685. (PMID: 25819065)
Sci STKE. 1999 Dec 21;1999(13):PE1. (PMID: 11865188)
Cell Signal. 2011 Nov;23(11):1794-805. (PMID: 21726627)
Cancer Cell. 2010 Dec 14;18(6):683-95. (PMID: 21156289)
Breast Cancer Res. 2010;12 (3):R29. (PMID: 20497549)
Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7421-6. (PMID: 10377430)
Trends Biochem Sci. 2001 Nov;26(11):657-64. (PMID: 11701324)
J Biol Chem. 2002 Aug 23;277(34):31099-106. (PMID: 12048182)
Cancer Res. 2009 May 15;69(10):4286-93. (PMID: 19401449)
Sci Signal. 2008 Jun 17;1(24):pe29. (PMID: 18560018)
Oncogene. 2011 Jun 2;30(22):2547-57. (PMID: 21278786)

0 (FOXO1 protein, human)
0 (Forkhead Box Protein O1)
EC 2.7.1.- (MAP2K2 protein, human)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
EC 2.7.12.2 (MAP Kinase Kinase 1)
EC 2.7.12.2 (MAP Kinase Kinase 2)
EC 2.7.12.2 (MAP2K1 protein, human)

Date Created: 20170223 Date Completed: 20181029 Latest Revision: 20191210

20231215

PMC5320536

10.1038/srep43078

28225038