title: 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 occurs 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 found that tension imposed on JAM-A activates RhoA, which leads to increased cell stiffness. Activation of RhoA in this system depends 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 Ser-284 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.
authors.affiliation: Department of Cell Biology and Physiology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 dwscott@email.unc.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.affiliation: Department of Cell Biology and Physiology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Tolbert
authors.affiliation: Department of Cell Biology and Physiology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Keith
authors.initials: K
authors.lastname: Burridge
mesh_terms: D015815:Cell Adhesion Molecules; D018929:Cell Culture Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D062745:Junctional Adhesion Molecule A / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D040542:Mechanotransduction, Cellular / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D019061:src-Family Kinases
chemical_list: C576600:ARHGEF1 protein, human; C577356:ARHGEF2 protein, human; D015815:Cell Adhesion Molecules; D020662:Guanine Nucleotide Exchange Factors; D062745:Junctional Adhesion Molecule A; D064067:Rho Guanine Nucleotide Exchange Factors; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D020742:rhoA GTP-Binding Protein