title: MLK4β functions as a negative regulator of MAPK signaling and cell invasion.
abstract: Mixed lineage kinase (MLK) 4, or MLK4, is a member of the MLK family of mitogen-activated protein kinase kinase kinases (MAP3Ks). Typically, MAP3Ks function to activate the mitogen-activated protein kinase (MAPK)-signaling pathways and regulate different cellular responses. However, here we report that MLK4β, unlike the other MLKs, negatively regulates the activities of the MAPKs, p38, c-Jun N-terminal kinase and extracellular signal-regulated kinase, and the MAP2Ks, MEK3 and 6. Our results show that MLK4β inhibits sorbitol- and tumor necrosis factor-induced activation of p38. Furthermore, MLK4β interacts with another MLK family member, MLK3, in HCT116 cells. Exogenous expression of MLK4β inhibits activation of MLK3 and also blocks matrix metalloproteinase-9 gelatinase activity and invasion in SKOV3 ovarian cancer cells. Collectively, our data establish MLK4β as a novel suppressor of MLK3 activation, MAPK signaling and cell invasion.
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, OH, USA.
authors.forename: W F
authors.initials: WF
authors.lastname: Abi Saab
authors.forename: M S
authors.initials: MS
authors.lastname: Brown
authors.forename: D N
authors.initials: DN
authors.lastname: Chadee
references.citation: J Biol Chem. 1995 Mar 31;270(13):7420-6
references.pmid: 7535770
references.citation: Oncogene. 2007 Mar 29;26(14):2133-5
references.pmid: 17016444
references.citation: EMBO J. 1997 Jan 15;16(2):295-305
references.pmid: 9029150
references.citation: Cell Mol Immunol. 2012 Jan;9(1):27-33
references.pmid: 21602844
references.citation: Neurochem Res. 2005 Dec;30(12):1589-97
references.pmid: 16362778
references.citation: Dig Liver Dis. 2006 Apr;38(4):283
references.pmid: 16309983
references.citation: Nat Rev Mol Cell Biol. 2002 Sep;3(9):663-72
references.pmid: 12209126
references.citation: J Biol Chem. 2008 Sep 5;283(36):24949-61
references.pmid: 18586681
references.citation: J Biol Chem. 1999 Jul 30;274(31):21491-4
references.pmid: 10419448
references.citation: Nature. 1994 Dec 22-29;372(6508):739-46
references.pmid: 7997261
references.citation: J Biol Chem. 2005 Apr 15;280(15):14675-83
references.pmid: 15677464
references.citation: Science. 2003 May 9;300(5621):949
references.pmid: 12738854
references.citation: Nat Cell Biol. 2004 Aug;6(8):770-6
references.pmid: 15258589
references.citation: Endocr Rev. 2001 Apr;22(2):153-83
references.pmid: 11294822
references.citation: Mol Cell. 2008 Oct 10;32(1):43-56
references.pmid: 18851832
references.citation: Clin Cancer Res. 2001 Aug;7(8):2396-404
references.pmid: 11489818
references.citation: Physiol Rev. 2001 Apr;81(2):807-69
references.pmid: 11274345
references.citation: Science. 2002 Dec 6;298(5600):1911-2
references.pmid: 12471242
references.citation: Mol Cell Biol. 1996 Mar;16(3):1247-55
references.pmid: 8622669
references.citation: Curr Biol. 1998 Sep 24;8(19):1049-57
references.pmid: 9768359
references.citation: Mol Cell Biol. 2005 May;25(9):3670-81
references.pmid: 15831472
references.citation: Oncogene. 2010 Aug 5;29(31):4399-411
references.pmid: 20514022
references.citation: Curr Biol. 1998 Dec 17-31;8(25):1387-90
references.pmid: 9889102
references.citation: Genomics Insights. 2011 Mar 22;4:1-12
references.pmid: 26217104
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Biochem Cell Biol. 2004 Dec;82(6):658-63
references.pmid: 15674433
references.citation: J Biol Chem. 2005 Dec 30;280(52):42984-93
references.pmid: 16253996