title: 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.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Dusaban
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jhbrown@ucsd.edu.
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
mesh_terms: D000818:Animals; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010716:Phosphatidylinositols / Q000235:genetics / Q000378:metabolism; D054801:Phosphoinositide Phospholipase C / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000089804:Shelterin Complex; D015398:Signal Transduction; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D010716:Phosphatidylinositols; D043562:Receptors, G-Protein-Coupled; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; C066737:RHOA protein, human; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; D020742:rhoA GTP-Binding Protein
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