Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation.
F-actin polymerization following engagement of the T cell receptor (TCR) is dependent on WASP and is critical for T cell activation. The link between TCR and WASP is not fully understood. In resting cells, WASP exists in a complex with WIP, which inhibits its activation by Cdc42. We show that the adaptor protein CrkL binds directly to WIP. Further, TCR ligation results in the formation of a ZAP-70-CrkL-WIP-WASP complex, which is recruited to lipid rafts and the immunological synapse. TCR engagement also causes PKCtheta-dependent phosphorylation of WIP, causing the disengagement of WASP from the WIP-WASP complex, thereby releasing it from WIP inhibition. These results suggest that the ZAP-70-CrkL-WIP pathway and PKCtheta link TCR to WASP activation.
Sasahara
Yoji
Y
Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Rachid
Rima
R
Byrne
Michael J
MJ
de la Fuente
Miguel A
MA
Abraham
Robert T
RT
Ramesh
Narayanaswamy
N
Geha
Raif S
RS
D000199:Actins / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology; D002460:Cell Line; D003598:Cytoskeletal Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D064546:Protein Kinase C beta; D021381:Protein Transport; D011506:Proteins / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured; D014923:Wiskott-Aldrich Syndrome / Q000276:immunology / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D000199:Actins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C495767:WAS protein, human; C109903:WIPF1 protein, human; C495768:Was protein, mouse; C491671:Waspip protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D020764:cdc42 GTP-Binding Protein