PLC[varepsilon] mediated sustained signaling pathways

Phospholipase C-[varepsilon] (PLC[varepsilon]) integrates signaling from G-protein coupled receptors (GPCRs) to downstream kinases to regulate a broad range of biological and pathophysiological responses. Relative to other PLCs, PLC[varepsilon] is unique in that it not only serves a catalytic function in phosphoinositide hydrolysis but also functions as an exchange factor small the low molecular weight G-protein Rap1. PLC[varepsilon] is selectively stimulated by agonists for GPCRs that couple to RhoA, which bind directly to the enzyme to regulate its activity. Rap1 also regulates PLC[varepsilon] activity by binding to its RA2 domain and this generates a feedback mechanism allowing sustained signaling. As a result of its regulation by inflammatory ligands for GPCRs and its ability to promote chronic signals, PLC[varepsilon] has been implicated in diseases ranging from cancer to ischemia/reperfusion injury. This review will discuss the regulation of PLC[varepsilon], molecular mechanisms that contribute to sustained signaling, and the role of the enzyme in various disease contexts.