title: Filamin A is required for T cell activation mediated by protein kinase C-theta.
abstract: Induction of T cell responses following engagement of the Ag-specific TCR depends on TCR-initiated rearrangements of the cellular actin cytoskeleton and highly coordinated and tightly regulated interactions and of diverse intracellular signaling proteins. In this study, we show that filamin A (FLNa), an actin-binding and signal mediator scaffolding protein, is required for T cell activation. Following Ag stimulation, FLNa was recruited to the T cell-APC contact area, where it colocalized with protein kinase C-theta (PKCtheta). Depletion of FLNa by RNA interference did not affect TCR-induced early tyrosine phosphorylation or actin polymerization but, nevertheless, resulted in impaired IL-2 expression by human primary T cells and reduced activation of NF-kappaB, AP-1, and NFAT reporter genes in transfected T cells. TCR stimulation induced stable physical association of FLNa with PKCtheta. Furthermore, the TCR/CD28-induced membrane translocation of PKCtheta was inhibited in FLNa-depleted T cells. These results reveal novel role for FLNa in the TCR/CD28 signaling pathway leading to transcription factor activation and IL-2 production, and suggest that this role is mediated, in part, through the inducible interaction of FLNa with PKCtheta.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Amnon
authors.initials: A
authors.lastname: Altman
mesh_terms: D000938:Antigen-Presenting Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000502:physiology; D002450:Cell Communication / Q000276:immunology; D002462:Cell Membrane / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003285:Contractile Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003600:Cytosol / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D064448:Filamins; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000074121:Protein Kinase C-theta; D021381:Protein Transport; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D003285:Contractile Proteins; D064448:Filamins; D007376:Interleukin-2; D007527:Isoenzymes; D008840:Microfilament Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta