PKC theta mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia

Protein kinase (PK)Ctheta is a critical regulator of mature T-cell activation and proliferation, being implicated in TCR-triggered nuclear factor (NF)-kB activation and providing important survival signals to leukemic T cells. We previously showed that overexpression of pTalpha/pre- TCR and constitutive activation of NF-kB characterize the T-cell leukemia/lymphoma developing in Notch3-IC transgenic mice. We report here that PKCtheta is a downstream target of Notch3 signaling and that its activation and membrane translocation require a functional pre-TCR in order to trigger NF-kB activation in thymocytes and lymphoma cells of transgenic mice. Furthermore, deletion of PKCtheta in Notch3-IC transgenic mice reduces the incidence of leukemia, correlating with decreased NF-kB activation. This paper therefore suggests that PKCtheta mediates the activation of NF-kB by pre-TCR in immature thymocytes and contributes to the development of Notch3-dependent T-cell lymphoma.