Protein kinase C-θ mediates a selective T cell survival signal via phosphorylation of BAD

Protein kinase C (PKC)-activating phorbol esters protect T cells from Fas-induced apoptosis. However, the mechanism of this protective effect and the identity of the relevant PKC isoform(s) are poorly understood. Here, we show that PKC theta plays a selective and important role in this protection. Pas triggering led to a selective caspase-3-dependent cleavage of the enzyme and proteasome-mediated degradation and inactivation of its catalytic fragment. These events preceded the onset of apoptosis. Pharmacological inhibition of PKC theta promoted Fas-mediated apoptosis in three different types of T cells. Conversely, constitutively active PKC theta (and, to a lesser degree, PKC epsilon) selectively protected T cells from Fas-induced apoptosis. We provide evidence that the distant Bcl-2 family member, BAD, is a PKC theta substrate, is phosphorylated by TCR stimulation, and can mediate at least in part the anti-apoptotic effect of PKC theta.