Phosphotyrosine-dependent interaction between the kinases PKC{theta} and Zap70 promotes proximal TCR signaling

Protein kinase C- (PKC) is an important component of proximal T cell receptor (TCR) signaling. We previously identified the amino-terminal C2 domain of PKC as a phosphotyrosine (pTyr)–binding domain. Using a mutant form of PKC that cannot bind pTyr (PKCHR2A), we showed that pTyr binding by PKC 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 -associated protein kinase of 70 kDa (Zap70) as a binding partner of the PKC pTyr-binding pocket. Tyr126 of Zap70 directly bound to PKC, and the interdomain B residues Tyr315 and Tyr319 were indirectly required for binding to PKC, reflecting their role in promoting the open conformation of Zap70. PKCHR2A-expressing CD4+ T cells displayed defects not only in known PKC-dependent signaling events, such as nuclear factor B (NF-B) 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-1 (PLC1), signaling proteins that are traditionally considered to be activated independently of PKC. These findings demonstrate that PKC 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 PKC in T cell Ca2+ signaling. Thi...
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Articles Source Type: news