[No authors listed]
Protein kinase C-θ is an important component of proximal T cell receptor (TCR) signaling. We previously identified the amino-terminal C2 domain of as a phosphotyrosine (pTyr)-binding domain. Using a mutant form of duanyu1531θ that cannot bind pTyr we showed that pTyr binding by duanyu1531θ was required for TCR-induced T cell activation, proliferation, and TH2 cell differentiation but not for T cell development. Using tandem mass spectrometry and coimmunoprecipitation, we identified the kinase ζ-associated protein kinase of 70 kDa (Zap70) as a binding partner of the duanyu1531θ pTyr-binding pocket. Tyr126 of Zap70 directly bound to and the interdomain B residues Tyr315 and Tyr319 were indirectly required for binding to duanyu1531θ, reflecting their role in promoting the open conformation of Zap70. CD4+ T cells displayed defects not only in known signaling events, such as nuclear factor κB (NF-κB) activation and TH2 cell differentiation, but also in full activation of Zap70 itself and in the activating phosphorylation of linker of activation of T cells (LAT) and phospholipase C-γ1 (PLCγ1), signaling proteins that are traditionally considered to be activated independently of These findings demonstrate that duanyu1531θ plays an important role in a positive feedback regulatory loop that modulates TCR-proximal signaling and, moreover, provide a mechanistic explanation for earlier reports that documented an important role for duanyu1531θ in T cell Ca2+ signaling. This interaction could potentially serve as a promising and highly selective immunosuppressive drug target in autoimmunity and organ transplantation.
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