title: Molecular controls of antigen receptor clustering and autoimmunity.
abstract: Cellular organization of the cytoskeleton, assembly of intracellular signaling complexes and movement of membrane receptors into supramolecular activation complexes (SMACs) are crucial prerequisites for lymphocyte activation and function. Full T-cell activation requires costimulatory signals in addition to antigen-mediated signals. Costimulatory signals facilitate T-cell activation by inducing SMAC formation, resulting in sustained signal transduction, cell-cycle progression and cytokine production. The guanine nucleotide exchange factor Vav1 and the Wiscott-Aldrich syndrome protein (WASP) regulate the actin cytoskeleton in T cells and also regulate SMAC formation. In mice lacking the E3 ubiquitin ligase Cbl-b, the Vav-WASP signaling pathway is active in the absence of costimulation resulting in deregulated cytoskeletal reorganization, enhanced priming and expansion of autoreactive T cells, and the development of autoimmunity. This review discusses the role of Cbl-b, Vav and WASP in the regulation of SMAC formation and the implications for the maintenance of tolerance and the development of autoimmunity.
authors.affiliation: Dept of Medical Biophysics, Amgen Institute/Ontario Cancer Institute, University of Toronto, 620 University Avenue, M5G 2C1, Toronto, Ontario, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Krawczyk
authors.forename: J M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015551:Autoimmunity / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D003599:Cytoskeleton / Q000378:metabolism*; D006801:Humans; D046911:Macromolecular Substances; D018448:Models, Immunological; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D051567:Proto-Oncogene Proteins c-vav; D011940:Receptor Aggregation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases; D051316:Wiskott-Aldrich Syndrome Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D046911:Macromolecular Substances; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496618:VAV1 protein, human; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases