PKCε is a permissive link in integrin-dependent IFN-γ signalling that facilitates JAK phosphorylation of STAT1

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Abstract
The critical dependence of receptor-triggered signals on integrin-mediated cell–substrate interactions represents a fundamental biological paradigm in health and disease. However, the molecular connections of these permissive inputs, which operate through integrin–matrix interactions, has remained largely obscure. Here we show that the serine-threonine kinase protein kinase C ε (PKCε) functions as a signal integrator between cytokine and integrin signalling pathways. Integrins are shown to control PKCε phosphorylation acutely by determining complex formation with protein phosphatase 2A (PP2A) and the upstream kinase PDK1 (phosphoinositide-dependent kinase 1). The PP2A-induced loss of PKCε function results in attenuated interferon γ (INF-γ)-induced phosphorylation of STAT1 (signal transducer and activator of transcription 1) downstream of Janus kinase 1/2 (JAK1/2). PKCε function and the IFN-γ response can be recovered by inhibition of PP2A if PDK1 is associated with PKCε in this complex. More directly, a PP2A-resistant mutant of PKCε is sufficient for restoration of the IFN-γ response in suspension culture. Thus, PKCε functions as a central point of integration through which integrin engagement exerts a permissive input on IFN-γ signalling.