Removal of C-terminal SRC kinase from the immune synapse by a new binding protein.
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.
Rahmouni
Souad
S
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.
Vang
Torkel
T
Alonso
Andres
A
Williams
Scott
S
van Stipdonk
Marianne
M
Soncini
Chiara
C
Moutschen
Michel
M
Schoenberger
Stephen P
SP
Mustelin
Tomas
T
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
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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