PKCθ 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)-kappaB activation and providing important survival signals to leukemic T cells. We previously showed that overexpression of pTalpha/pre-TCR and constitutive activation of NF-kappaB 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-kappaB 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-kappaB activation. This paper therefore suggests that PKCtheta mediates the activation of NF-kappaB by pre-TCR in immature thymocytes and contributes to the development of Notch3-dependent T-cell lymphoma.