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.
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.
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DOI：
10.1084/jem.20030976
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发表时间：
2004-01-05
期刊：
影响因子：
--
通讯作者：
Siminovitch KA
中科院分区：
文献类型：
--
作者：
Badour K;Zhang J;Shi F;Leng Y;Collins M;Siminovitch KA
Wiskott-Aldrich综合征蛋白（WASp）参与促进细胞活化需要其从自身抑制结构限制中释放，并已归因于WASp与活化的cdc 42相关。然而，在这里，我们发现T细胞发育和T细胞受体（TCR）诱导的增殖和肌动蛋白聚合在表达缺乏cdc 42结合结构域的WASp转基因的WASp−/−小鼠中正常进行。相反，酪氨酸残基Y291的突变，这里确定为TCR诱导的WASp酪氨酸磷酸化的主要位点，废除WASp酪氨酸磷酸化的诱导及其效应活性，包括活化的T细胞转录活性的核因子，肌动蛋白聚合和免疫突触形成。TCR诱导的WASp酪氨酸磷酸化在缺乏Fyn的T细胞中也被破坏，Fyn是一种与WASp结合、共定位和磷酸化的激酶。相比之下，WASp被蛋白酪氨酸磷酸酶（PTP）-PEST酪氨酸去磷酸化，这里显示的酪氨酸磷酸酶通过脯氨酸、丝氨酸、苏氨酸磷酸酶相互作用蛋白（PSTPIP）1结合与WASp相互作用。虽然Fyn增强了WASP介导的Arp 2/3激活，并且是突触形成所必需的，但PTP-PEST与PSTPIP 1结合抑制了WASP驱动的肌动蛋白聚合和突触形成。这些观察结果确定了Fyn和PTP-PEST在调节WASp中的关键作用，并暗示诱导型WASp酪氨酸磷酸化可以独立于cdc 42结合而发生，但与cdc 42相互作用不同，WASp对T细胞活化的贡献是绝对必需的。
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.
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