| First Author | Xie J | Year | 2019 |
| Journal | Sci Signal | Volume | 12 |
| Issue | 577 | PubMed ID | 30992398 |
| Mgi Jnum | J:284348 | Mgi Id | MGI:6380898 |
| Doi | 10.1126/scisignal.aar3349 | Citation | Xie J, et al. (2019) Phosphotyrosine-dependent interaction between the kinases PKCtheta and Zap70 promotes proximal TCR signaling. Sci Signal 12(577) |
| abstractText | Protein kinase C-theta (PKCtheta) is an important component of proximal T cell receptor (TCR) signaling. We previously identified the amino-terminal C2 domain of PKCtheta as a phosphotyrosine (pTyr)-binding domain. Using a mutant form of PKCtheta that cannot bind pTyr (PKCtheta(HR2A)), we showed that pTyr binding by PKCtheta 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 zeta-associated protein kinase of 70 kDa (Zap70) as a binding partner of the PKCtheta pTyr-binding pocket. Tyr(126) of Zap70 directly bound to PKCtheta, and the interdomain B residues Tyr(315) and Tyr(319) were indirectly required for binding to PKCtheta, reflecting their role in promoting the open conformation of Zap70. PKCtheta(HR2A)-expressing CD4(+) T cells displayed defects not only in known PKCtheta-dependent signaling events, such as nuclear factor kappaB (NF-kappaB) 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-gamma1 (PLCgamma1), signaling proteins that are traditionally considered to be activated independently of PKC. These findings demonstrate that PKCtheta 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 PKCtheta in T cell Ca(2+) signaling. This PKCtheta-Zap70 interaction could potentially serve as a promising and highly selective immunosuppressive drug target in autoimmunity and organ transplantation. |
