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

• Published in: Biochimica et biophysica acta Vol. 1843; no. 5; pp. 945 - 954
• Main Authors: Mirza, Ahmed A., Kahle, Michael P., Ameka, Magdalene, Campbell, Edward M., Cuevas, Bruce D.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-05-2014
• Subjects: Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Female; Fibronectin; Fibronectins - metabolism; Focal adhesion; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Focal Adhesions - physiology; Gene Silencing; Humans; Kinase; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - physiology; MEKK2; Neoplasm Invasiveness; Phosphorylation; Kinase; Fibronectin; MEKK2; Focal adhesion
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2014.01.029

MEK Kinase 2 (MEKK2) is a serine/threonine kinase that functions as a MAPK kinase kinase (MAP3K) to regulate activation of Mitogen-activated Protein Kinases (MAPKs). 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 Extracellular Signal-Regulated Kinase 5 (ERK5) signaling and Focal Adhesion Kinase (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.
•Cellular attachment to matrix proteins recruits MEKK2 to focal adhesions.•MEKK2 regulates focal adhesion stability and migration in breast tumor cells.•MEKK2 regulates fibronectin-induced ERK5 and FAK phosphorylation.