HLA class I signal transduction is dependent on Rho GTPase and ROK.
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.
Lepin
Eric J
EJ
UCLA Immunogenetics Center, David Geffen School of Medicine, University of California, Los Angeles, 1000 Veteran Avenue, Los Angeles, CA 90095, USA.
Jin
Yi-Ping
YP
Barwe
Sonali P
SP
Rozengurt
Enrique
E
Reed
Elaine F
EF
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
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