PLCε mediated sustained signaling pathways

Abstract

Phospholipase C-ε (PLCε) 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, PLCε 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. PLCε is selectively stimulated by agonists for GPCRs that couple to RhoA, which bind directly to the enzyme to regulate its activity. Rap1 also regulates PLCε 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, PLCε has been implicated in diseases ranging from cancer to ischemia/reperfusion injury. This review will discuss the regulation of PLCε, molecular mechanisms that contribute to sustained signaling, and the role of the enzyme in various disease contexts.

Keywords: Diacylglycerol (DAG); G-protein coupled receptors (GPCRs); Golgi; Inositol 1,4,5-trisphosphate (IP3); Phosphatidylinositol4,5-bisphosphate (PIP2); Phospholipase C-ε (PLCε); Protein kinase D(PKD); Rap1; Ras; RhoA.

Figure 1. Schema of PLCe mediated sustained signaling

In response to activation of GPCRs that couple to Gα_12/13, activated Rho binds to a unique insert in the Y domain of PLCε to result in activation of downstream signaling kinases. The CDC25 domain of the enzyme, that functions as a Rap1 GEF, generates activated Rap1 that can then bind to the RA2 domain of PLCε and result in sustained activation of the enzyme. It has also been shown that Rap1 is important for PLCε’s localization to the Golgi and that this could mediate localized production of DAG and sustained activation of PKC and PKD.