SLP-76 coordinates Nck-dependent Wiskott-Aldrich syndrome protein recruitment with Vav-1/Cdc42-dependent Wiskott-Aldrich syndrome protein activation at the T cell-APC contact site.
We have shown previously that Wiskott-Aldrich syndrome protein (WASP) activation at the site of T cell-APC interaction is a two-step process, with recruitment dependent on the proline-rich domain and activation dependent on binding of Cdc42-GTP to the GTPase binding domain. Here, we show that WASP recruitment occurs through binding to the C-terminal Src homology 3 domain of Nck. In contrast, WASP activation requires Vav-1. In Vav-1-deficient T cells, WASP recruitment proceeds normally, but localized activation of Cdc42 and WASP is disrupted. The recruitment and activation of WASP are coordinated by tyrosine-phosphorylated Src homology 2 domain-containing leukocyte protein of 76 kDa, which functions as a scaffold, bringing Nck and WASP into proximity with Vav-1 and Cdc42-GTP. Taken together, these findings reconstruct the signaling pathway leading from TCR ligation to localized WASP activation.
Zeng
Rong
R
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Cannon
Judy L
JL
Abraham
Robert T
RT
Way
Michael
M
Billadeau
Daniel D
DD
Bubeck-Wardenberg
Julie
J
Burkhardt
Janis K
JK
D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D018797:Cell Cycle Proteins; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism / Q000502:physiology*; D017354:Point Mutation; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D014923:Wiskott-Aldrich Syndrome / Q000276:immunology / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism / Q000502:physiology*; D018909:src Homology Domains / Q000235:genetics
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C078332:Nck protein; D015513:Oncogene Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C092947:SLP-76 signal Transducing adaptor proteins; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; C495767:WAS protein, human; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D014443:Tyrosine; D020764:cdc42 GTP-Binding Protein