title: HLA class I signal transduction is dependent on Rho GTPase and ROK.
abstract: Chronic rejection is the major limitation to long-term allograft survival. HLA class I signaling pathways have been implicated in this process because ligation of class I molecules by anti-HLA antibodies (Ab) initiates intracellular signals in smooth muscle cells (SMC) and endothelial cells (EC) that synergize with growth factor receptors to elicit cell survival and proliferation. Anti-HLA Ab mediate cell proliferation and survival through a focal adhesion kinase dependent pathway that requires the integrity of the actin cytoskeleton. In this study, we investigated the role of Rho and Rho-kinase (ROK) in class I signal transduction. We show that class I ligation results in activation of Rho and increased stress fiber formation. In addition, inhibitors of Rho GTPase and ROK block HLA class I-mediated tyrosyl phosphorylation of paxillin and FAK, central elements of the focal adhesion signaling complex. These results suggest that HLA class I-induced signaling in EC is dependent on Rho GTPase and ROK.
authors.affiliation: UCLA Immunogenetics Center, David Geffen School of Medicine, University of California, Los Angeles, 1000 Veteran Avenue, Los Angeles, CA 90095, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lepin
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Jin
authors.forename: Sonali P
authors.initials: SP
authors.lastname: Barwe
authors.forename: Enrique
authors.initials: E
authors.lastname: Rozengurt
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Reed
mesh_terms: D000199:Actins / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D006801:Humans; D006825:Hybridomas / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D009130:Muscle, Smooth / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D051419:Paxillin; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins