Tension on JAM-A activates RhoA via GEF-H1 and p115 RhoGEF.

Abstract Junctional Adhesion Molecule A (JAM-A) is a broadly expressed adhesion molecule that regulates cell-cell contacts and facilitates leukocyte transendothelial migration; the latter occurring through interactions with the integrin LFA-1. Although we understand much about JAM-A, little is known regarding the protein's role in mechanotransduction or as a modulator of RhoA signaling. We have found that tension imposed on JAM-A activates RhoA which leads to increased cell stiffness. Activation of RhoA in this system is dependent on PI3K-mediated activation of GEF-H1 and p115 RhoGEF. These two GEFs are further regulated by FAK/ERK and Src family kinases, respectively. Finally, we show that phosphorylation of JAM-A at Ser284 is required for RhoA activation in response to tension. These data demonstrate a direct role of JAM-A in mechanosignaling and control of RhoA, and implicate Src family kinases in the regulation of p115 RhoGEF.