title: Removal of C-terminal SRC kinase from the immune synapse by a new binding protein.
abstract: The Csk tyrosine kinase negatively regulates the Src family kinases Lck and Fyn in T cells. Engagement of the T-cell antigen receptor results in a removal of Csk from the lipid raft-associated transmembrane protein PAG/Cbp. Instead, Csk becomes associated with an approximately 72-kDa tyrosine-phosphorylated protein, which we identify here as G3BP, a phosphoprotein reported to bind the SH3 domain of Ras GTPase-activating protein. G3BP reduced the ability of Csk to phosphorylate Lck at Y505 by decreasing the amount of Csk in lipid rafts. As a consequence, G3BP augmented T-cell activation as measured by interleukin-2 gene activation. Conversely, elimination of endogenous G3BP by RNA interference increased Lck Y505 phosphorylation and reduced TCR signaling. In antigen-specific T cells, endogenous G3BP moved into a intracellular location adjacent to the immune synapse, but deeper inside the cell, upon antigen recognition. Csk colocalization with G3BP occurred in this "parasynaptic" location. We conclude that G3BP is a new player in T-cell-antigen receptor signaling and acts to reduce the amount of Csk in the immune synapse.
authors.affiliation: Program of Inflammation, Infectious and Inflammatory Disease Center, and Program of Signal Transduction, Cancer Center, The Burnham Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037, USA.
authors.forename: Souad
authors.initials: S
authors.lastname: Rahmouni
authors.forename: Torkel
authors.initials: T
authors.lastname: Vang
authors.forename: Andres
authors.initials: A
authors.lastname: Alonso
authors.forename: Scott
authors.initials: S
authors.lastname: Williams
authors.forename: Marianne
authors.initials: M
authors.lastname: van Stipdonk
authors.forename: Chiara
authors.initials: C
authors.lastname: Soncini
authors.forename: Michel
authors.initials: M
authors.lastname: Moutschen
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Schoenberger
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology / Q000502:physiology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010770:Phosphotransferases / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D000075223:Poly-ADP-Ribose Binding Proteins; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D034741:RNA, Small Interfering / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D013601:T-Lymphocytes / Q000737:chemistry / Q000201:enzymology* / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology; D019061:src-Family Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017252:CD3 Complex; D002352:Carrier Proteins; D008024:Ligands; D008565:Membrane Proteins; C498710:PAG1 protein, human; D010750:Phosphoproteins; D000075223:Poly-ADP-Ribose Binding Proteins; D011518:Proto-Oncogene Proteins; D000067776:RNA Recognition Motif Proteins; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D010770:Phosphotransferases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; C000631346:CSK protein, human; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases
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