Recruitment of Dok-R to the EGF receptor through its PTB domain is required for attenuation of Erk MAP kinase activation
Recruitment of Dok-R to the EGF receptor through its PTB domain is required for attenuation of Erk MAP kinase activation
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DOI：
10.1016/s0960-9822(99)80458-8
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发表时间：
1999-09-23
期刊：
影响因子：
9.2
通讯作者：
Dumont, DJ
中科院分区：
文献类型：
--
作者：
Jones, N;Dumont, DJ
Dok（酪氨酸激酶的下游）蛋白是一个新发现的对接分子家族，其特征是存在一个氨基末端pleckstrin同源（PH）结构域、一个中心推定的磷酸酪氨酸结合（PTB）结构域和许多潜在的酪氨酸磷酸化位点[1-6]。在这里，我们探讨了Dok家族成员Dok- r（也称为p56（Dok2）或FRIP）在表皮生长因子（EGF）受体介导的信号通路中的潜在作用。Dok-R中完整的PTB结构域对其与EGF受体上的两个PTB结合一致位点的关联至关重要，PH结构域进一步促进了Dok-R在体内的稳定结合和酪氨酸磷酸化。磷酸化Tyr276和Tyr304被认为连接p21(Ras) gtpase激活蛋白rasGAP的串联Src同源性2 （SH2）结构域，Tyr351介导与适配器蛋白Nck的SH2结构域的关联。有趣的是，我们发现Dok-R可以减弱egf刺激的丝裂原活化蛋白（MAP）激酶的激活，而不依赖于其与rasGAP的关联。总之，这些结果表明，Dok-R作为信号转导的潜在负调节因子，在生长因子受体的下游具有重要作用。
Dok (for downstream of tyrosine kinases) proteins are a newly identified family of docking molecules that are characterized by the presence of an amino-terminal pleckstrin homology (PH) domain, a central putative phosphotyrosine binding (PTB) domain and numerous potential sites of tyrosine phosphorylation [1-6]. Here, we explore the potential role of the Dok family member Dok-R (also known as p56(Dok2) or FRIP) in signaling pathways mediated by the epidermal growth factor (EGF) receptor. An intact PTB domain in Dok-R was critical for its association with two PTB-binding consensus sites on the EGF receptor and the PH domain further contributed to stable in vivo binding and tyrosine phosphorylation of Dok-R, Multiple sites on Dok-R were tyrosine-phosphorylated following EGF stimulation; phosphorylated Tyr276 and Tyr304 are proposed to dock the tandem Src homology 2 (SH2) domains of the p21(Ras) GTPase-activating protein rasGAP and Tyr351 mediates an association with the SH2 domain of the adapter protein Nck. lnterestingly, we have found that Dok-R could attenuate EGF-stimulated mitogen-activated protein (MAP) kinase activation independently of its association with rasGAP. Together, these results suggest that Dok-R has an important role downstream of growth factor receptors as a potential negative regulator of signal transduction.