Fyn and PTP-PEST-mediated regulation of Wiskott-Aldrich syndrome protein (WASp) tyrosine phosphorylation is required for coupling T cell antigen receptor engagement to WASp effector function and T cell activation.
Involvement of the Wiskott-Aldrich syndrome protein (WASp) in promoting cell activation requires its release from autoinhibitory structural constraints and has been attributed to WASp association with activated cdc42. Here, however, we show that T cell development and T cell receptor (TCR)-induced proliferation and actin polymerization proceed normally in WASp-/- mice ... expressing a WASp transgene lacking the cdc42 binding domain. By contrast, mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation. TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. By contrast, WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST, a tyrosine phosphatase shown here to interact with WASp via proline, serine, threonine phosphatase interacting protein (PSTPIP)1 binding. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation. These observations identify key roles for Fyn and PTP-PEST in regulating WASp and imply that inducible WASp tyrosine phosphorylation can occur independently of cdc42 binding, but unlike the cdc42 interaction, is absolutely required for WASp contributions to T cell activation.
Mesh Terms:
Animals, Crosses, Genetic, Gene Deletion, Humans, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Phosphotyrosine, Protein Tyrosine Phosphatase, Non-Receptor Type 12, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-fyn, Receptors, Antigen, T-Cell, T-Lymphocytes, Wiskott-Aldrich Syndrome, Wiskott-Aldrich Syndrome Protein
Animals, Crosses, Genetic, Gene Deletion, Humans, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Phosphotyrosine, Protein Tyrosine Phosphatase, Non-Receptor Type 12, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-fyn, Receptors, Antigen, T-Cell, T-Lymphocytes, Wiskott-Aldrich Syndrome, Wiskott-Aldrich Syndrome Protein
J. Exp. Med.
Date: Jan. 05, 2004
PubMed ID: 14707117
View in: Pubmed Google Scholar
Download Curated Data For This Publication
214166
Switch View:
- Interactions 5