Research ArticleImmunology

Phosphotyrosine-dependent interaction between the kinases PKCθ and Zap70 promotes proximal TCR signaling

See allHide authors and affiliations

Science Signaling  16 Apr 2019:
Vol. 12, Issue 577, eaar3349
DOI: 10.1126/scisignal.aar3349

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

PKCθ zaps the immunological synapse

Protein kinase C-θ (PKCθ) translocates to the center of the immunological synapse in antigen-stimulated T cells and plays a role in their activation. Unlike other PKC isoforms, PKCθ and its closest relative PKCδ bind to phosphotyrosines through their N-terminal C2 domains. Xie et al. found that phosphotyrosine binding by the PKCθ C2 domain was required for T cell activation, proliferation, and TH2 cell differentiation. The C2 domain interacted with the phosphorylated form of the kinase Zap70, which is critical for signaling downstream of the T cell receptor (TCR). Phosphotyrosine binding by PKCθ was required for its recruitment to the immunological synapse and for Zap70-dependent TCR signaling. Given limited success in developing clinically useful, highly specific catalytic inhibitors of PKCθ or Zap70, targeting the PKCθ-Zap70 interaction may be an alternative strategy for developing selective immunosuppressive drugs.


Protein kinase C-θ (PKCθ) is an important component of proximal T cell receptor (TCR) signaling. We previously identified the amino-terminal C2 domain of PKCθ as a phosphotyrosine (pTyr)–binding domain. Using a mutant form of PKCθ that cannot bind pTyr (PKCθHR2A), we showed that pTyr binding by PKCθ 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 PKCθ pTyr-binding pocket. Tyr126 of Zap70 directly bound to PKCθ, and the interdomain B residues Tyr315 and Tyr319 were indirectly required for binding to PKCθ, reflecting their role in promoting the open conformation of Zap70. PKCθHR2A-expressing CD4+ T cells displayed defects not only in known PKCθ-dependent 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 PKC. These findings demonstrate that PKCθ 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 PKCθ in T cell Ca2+ signaling. This PKCθ-Zap70 interaction could potentially serve as a promising and highly selective immunosuppressive drug target in autoimmunity and organ transplantation.

View Full Text

Stay Connected to Science Signaling