Molecular and cellular analysis of PKC-theta mediated regulation of T cell functions

Project Details

Description

Abstract The PKCθ isoform is selectively enriched in T cells and platelets, and function as a key modulator of T cell receptor (TCR) signaling and an essential regulator of T cell activation and survival. In antigen-stimulated T cells, PKCθ selectively translocates to the center of the IS, where it mediates critical TCR and CD28 signals leading to the activation of NF-κB, AP-1 and NFAT transcription factors. A major focus of the present project was on the molecular mechanism that regulates the translocation of PKCθ to the center of the IS. We found that a proline-rich region within the unique V3 (hinge) domain of PKCθ recruits the enzyme to the cytoplasmic tail of CD28 in a TCR activation-dependent manner. The PKCθ-CD28 interaction is mediated via an indirect mechanism involving the Lck protein tyrosine kinase as an intermediate. Our studies revealed also a critical role of PKCθ in the regulation of platelet functions, which are essential for hemostatic plug formation following vascular injury, and respond to agonists, such as thrombin, a coagulation protease that activates PAR receptors on the surface of platelets. We found that PKC(-deficient C57BL/6J and BALB/C mice exhibit an impaired hemostasis, and prolonged bleeding following vascular injury. Their platelets displayed an impaired thrombin-induced activation and aggregation response, and impaired (-granule secretion. Since PAR4 is the only mouse PAR receptor that delivers thrombin-induced activation signals in platelets, our results indicate that PKC( is a critical effector molecule in the PAR4-linked signaling pathways and in the regulation of normal hemostasis in mice.

StatusActive
Effective start/end date1/01/07 → …

Funding

  • United States-Israel Binational Science Foundation (BSF)

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