MEKK2 regulates focal adhesion stability and motility in invasive breast cancer cells Journal Article

Authors: Mirza, A. A.; Kahle, M. P.; Ameka, M.; Campbell, E. M.; Cuevas, B. D.
Article Title: MEKK2 regulates focal adhesion stability and motility in invasive breast cancer cells
Abstract: MEKK2 is a serine/threonine kinase that functions as a MAPKinase kinase kinase (MAP3K) to regulate activation of MAP kinases. We recently have demonstrated that ablation of MEKK2 expression in invasive breast tumor cells dramatically inhibits xenograft metastasis, but the mechanism by which MEKK2 influences metastasis-related tumor cell function is unknown. In this study, we investigate MEKK2 function and demonstrate that silencing MEKK2 expression in breast tumor cell significantly enhances cell spread area and focal adhesion stability while reducing cell migration. We show that cell attachment to the matrix proteins fibronectin or Matrigel induces MEKK2 activation and localization to focal adhesions. Further, we reveal that MEKK2 ablation enhances focal adhesion size and frequency, thereby linking MEKK2 function to focal adhesion stability. Finally, we show that MEKK2 knockdown inhibits fibronectin-induced ERK5 signaling and FAK autophosphorylation. Taken together, our results strongly support a role for MEKK2 as a regulator of signaling that modulates breast tumor cell spread area and migration through control of focal adhesion stability.
Journal Title: Biochimica et biophysica acta
Volume: 1843
Issue: 5
ISSN: 0006-3002; 0006-3002
Publisher: Elsevier Inc  
Date Published: 2014
Start Page: 945
End Page: 954
Language: ENG
Notes: LR: 20150501; CI: Copyright (c) 2014; GR: CA120881/CA/NCI NIH HHS/United States; GR: K01 CA120881/CA/NCI NIH HHS/United States; JID: 0217513; 0 (Fibronectins); EC (Focal Adhesion Protein-Tyrosine Kinases); EC (MAP Kinase Kinase Kinases); EC (MAP3K2 protein, human); NIHMS562612; OID: NLM: NIHMS562612; OID: NLM: PMC3960922; OTO: NOTNLM; 2013/07/30 [received]; 2014/01/14 [revised]; 2014/01/24 [accepted]; 2014/01/31 [aheadofprint]; ppublish