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.
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November 2014
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Research Article|
October 23 2014
MEKK2 regulates paxillin ubiquitylation and localization in MDA-MB 231 breast cancer cells
Magdalene Ameka;
Magdalene Ameka
*Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, U.S.A.
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Michael P. Kahle;
Michael P. Kahle
*Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, U.S.A.
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Mathew Perez-Neut;
Mathew Perez-Neut
*Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, U.S.A.
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Saverio Gentile;
Saverio Gentile
*Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, U.S.A.
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Ahmed A. Mirza;
Ahmed A. Mirza
1
*Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, U.S.A.
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Bruce D. Cuevas
Bruce D. Cuevas
2
*Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, U.S.A.
2To whom correspondence should be addressed (email bcuevas@luc.edu).
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Biochem J (2014) 464 (1): 99–108.
Article history
Received:
April 01 2014
Revision Received:
August 12 2014
Accepted:
September 05 2014
Accepted Manuscript online:
September 05 2014
Citation
Magdalene Ameka, Michael P. Kahle, Mathew Perez-Neut, Saverio Gentile, Ahmed A. Mirza, Bruce D. Cuevas; MEKK2 regulates paxillin ubiquitylation and localization in MDA-MB 231 breast cancer cells. Biochem J 15 November 2014; 464 (1): 99–108. doi: https://doi.org/10.1042/BJ20140420
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