MEK kinase 2 regulates integrin signaling to control paxillin ubiquitylation and focal adhesion stability in breast tumor cells (797.3)

Abstract

We have recently shown by gene silencing in invasive breast tumor cells that the kinase MEKK2 is required for xenograft metastasis, and our objective in this work was to determine how MEKK2 influences tumor cell function. We discovered that silencing MEKK2 expression significantly inhibits tumor cell migration, and was associated with a marked increase in the number and size of focal adhesion complexes. We discovered that tumor cell attachment to fibronectin, but not collagen, induces MEKK2 activation and translocalization to focal adhesions. Furthermore, MEKK2 knockdown greatly reduces fibronectin‐induced focal adhesion kinase phosphorylation, suggesting that MEKK2 mediates integrin‐induced signaling. We reveal that MEKK2 associates with the scaffold protein paxillin in an interaction that requires the amino‐terminal leucine‐rich motif (LD1) of paxillin. We demonstrate that the MEKK2/paxillin complex promotes paxillin ubiquitylation and consequent re‐distribution to the cytoplasm, thereby promoting focal adhesion turnover and cell migration. Finally, we show that MEKK2 associates with the ubiquitin ligase RNF5 and promotes paxillin ubiquitylation. Taken together, our results reveal a novel function for MEKK2 as a regulator of ubiquitylation‐dependent paxillin redistribution that promotes focal adhesion turnover and breast tumor cell migration.Grant Funding Source: NIH CA120881