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Dynamic recruitment of PAK1 to the immunological synapse is mediated by PIX independently of SLP-76 and Vav1

Nature Immunology volume 6, pages 608–617 (2005)Cite this article

Abstract

T cell receptor engagement activates p21-activated kinase 1 (PAK1) through a LAT–SLP-76–Nck–Vav-Rac–dependent pathway. A second independent pathway involving a GIT-PIX-PAK1 trimolecular complex is also activated by T cell receptor ligation. Here we show a Vav-independent pathway exists that leads to PAK1 activation. In addition, PAK1, PIX and GIT1 were recruited to the T cell–antigen-presenting cell contact site independently of SLP-76 and Vav1. PAK1 recruitment to the T cell–antigen-presenting cell interface required interaction with PIX, which also led to optimal PLC-γ1 activation and T cell receptor–dependent transcriptional responses. These data indicate that a pathway involving the GIT-PIX-PAK1 complex has a crucial function in PAK1 activation by recruiting PAK1 to the immunological synapse.

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Figure 1: Vav-dependent and Vav-independent activation of PAK1 after TCR stimulation.
Figure 2: Differential requirement for Vav1 in Rac and Cdc42 activation after TCR stimulation.
Figure 3: Recruitment of the PBD of PAK1 to the T cell–APC contact site.
Figure 4: Recruitment of PAK1 to the T cell–APC contact site.
Figure 5: PAK1 is recruited to the T cell–APC contact site independently of SLP-76 and Vav.
Figure 6: The recruitment of PIX and GIT to T cell–APC contact site is independent of SLP-76 and Vav.
Figure 7: Recruitment of GFP-PAK1 to the T cell–APC contact site is mediated by its interaction with PIX.
Figure 8: Expression of SH3*-βPIX inhibits TCR-induced PLC-γ1 activation and the transcriptional response.

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Acknowledgements

The authors thank A. Defranco, M. Krummel, T. Brdicka and S. Levin for reading this manuscript and for comments, and J. Jacobelli for helping with analysis of microscopy data for some of these studies. Supported in part by the National Cancer Institute (CA72531 to A.W.).

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Authors and Affiliations

  1. Department of Medicine, Howard Hughes Medical Institute, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, 94143, California, USA

    Hyewon Phee & Arthur Weiss

  2. Program in Signal Transduction Research, The Burnham Institute, La Jolla, 92037, California, USA

    Robert T Abraham

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Correspondence to Arthur Weiss.

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Supplementary Fig. 1

Effects of Vav-C on endogenous Cdc42 activation and PAK in vitro kinase assay. (PDF 440 kb)

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Phee, H., Abraham, R. & Weiss, A. Dynamic recruitment of PAK1 to the immunological synapse is mediated by PIX independently of SLP-76 and Vav1. Nat Immunol 6, 608–617 (2005). https://doi.org/10.1038/ni1199

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