title: MEKK2 regulates paxillin ubiquitylation and localization in MDA-MB 231 breast cancer cells.
abstract: The intracellular kinase MEKK2 (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase kinase 2) is an upstream regulator of JNK (c-Jun N-terminal kinase), but additional functions for MEKK2 have not been well defined. Silencing MEKK2 expression in invasive breast tumour cells markedly inhibits xenograft metastasis, indicating that MEKK2 controls tumour cell function required for tumour progression. In our previous investigation of MEKK2 function, we discovered that tumour cell attachment to fibronectin recruits MEKK2 to focal adhesion complexes, and that MEKK2 knockdown is associated with stabilized focal adhesions and significant inhibition of tumour cell migration. In the present study we investigate MEKK2 function in focal adhesions and we report that MEKK2 physically associates with the LD1 motif of the focal adhesion protein paxillin. We reveal that MEKK2 induces paxillin ubiquitylation, and that this function requires both the paxillin LD1 motif and MEKK2 kinase activity. Finally, we demonstrate that MEKK2 promotes paxillin redistribution from focal adhesions into the cytoplasm, but does not promote paxillin degradation. Taken together, our results reveal a novel function for MEKK2 as a regulator of ubiquitylation-dependent paxillin redistribution in breast tumour cells.
authors.affiliation: *Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, U.S.A.
authors.forename: Magdalene
authors.initials: M
authors.lastname: Ameka
authors.affiliation: *Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, U.S.A.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kahle
authors.affiliation: *Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, U.S.A.
authors.forename: Mathew
authors.initials: M
authors.lastname: Perez-Neut
authors.affiliation: *Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, U.S.A.
authors.forename: Saverio
authors.initials: S
authors.lastname: Gentile
authors.affiliation: *Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, U.S.A.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Mirza
authors.affiliation: *Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, U.S.A.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Cuevas
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D061986:MCF-7 Cells; D051419:Paxillin / Q000032:analysis / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: C496061:PXN protein, human; D051419:Paxillin; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases; C482618:MAP3K2 protein, human