Research ArticleImmunology

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

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

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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.