The Wiskott-Aldrich syndrome protein
Subtitle: forging a link between actin polymerization and T cell activation.
Published: 2005
Language: eng
Number of pages: 203
Description: The Wiskott-Aldrich Syndrome protein (WASp) plays a key role in coupling T cell antigen receptor (TCR) engagement to T cell activation, a functional role realized by WASp interactions with multiple signaling effectors and by its capacity to evoke Arp2/3 complex-mediated actin polymerization. However, the mechanisms linking TCR engagement to WASp modulation of transcriptional activation and cytoskeletal rearrangement have not been well defined. Herein, we report that the protein tyrosine kinase Fyn in cooperation with the protein tyrosine phosphatase PEST play key roles in regulating the functional activation of WASp required for WASp contributions to T cell activation by modulating the inducible phosphorylation of tyrosine residue 291. We have demonstrated that Y291 mutation abrogates induction of WASp tyrosine phosphorylation and effector functions. Our data also reveal WASp interactions with SH3 domain-containing adaptors to be key to WASp effects on T cell behaviour. Specifically, the data show that the PSTPIP1 adaptor inducibly associates with WASp and the CD2 receptor and induces WASp translocation such that PSTPIP1, WASp and CD2 inducibly colocalize in the immunological synapse. These findings, together with the demonstration that both CD2-induced actin polymerization and TCR-induced synapse formation are abrogated in WASp-deficient cells, reveals a key role for WASp in synapse formation and suggest that PSTPIP1 acts downstream of CD2 to link CD2 engagement to the WASp-evoked actin polymerization required for synapse formation and sustained T cell activation. Similarly, our data reveals that intersectin 2 inducibly associates with WASp following TCR stimulation. Overexpression of intersectin 2 induces WASp translocation to endocytic vesicles where intersectin 2 colocalizes with WASp. Additionally, overexpression of intersectin 2 results in increased levels of induction of TCR internalization. These findings suggest that intersectin 2 targets WASp to endocytic vesicles following TCR stimulation where the two proteins function to link the clathrin endocytic machinery to WASp-mediated actin polymerization and TCR endocytosis. These data therefore provide novel insights into the spatial and temporal regulation of WASp function and establish a critical role for WASp in integrating TCR stimulatory signals with the cytoskeleton so as to enable T cell activation.
Notes: Thesis (Ph.D.)--University of Toronto, 2005.

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Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 2949.