Regulation of Phosphoinositide-specific Phospholipase C Isozymes

Abstract

The hydrolysis of a minor membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PIP2), 1The abbreviations used are: PIP2, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; PKC, protein kinase C; PLD, phospholipase D; PI 3-kinase, phosphoinositide 3-kinase; PH, pleckstrin homology; SH, Src homology; GTPγS, guanosine 5′-3-O-(thio)triphosphate; IL, interleukin; PDGF, platelet-derived growth factor; PTK, protein tyrosine kinase; AA, arachidonic acid; PC, phosphatidylcholine; cPLA2, cytosolic phospholipase A2; PIP3, phosphatidylinositol 3,4,5-trisphosphate; α1-AR, α1-adrenergic receptor(s); PKA, cAMP-dependent protein kinase. by a specific phospholipase C (PLC) is one of the earliest key events in the regulation of various cell functions by more than 100 extracellular signaling molecules (1Rhee S.G. Choi K.D. J. Biol. Chem. 1992; 267: 12393-12396Abstract Full Text PDF PubMed Google Scholar, 2Cockcroft S. Thomas G.M.H. Biochem. J. 1992; 288: 1-14Crossref PubMed Scopus (371) Google Scholar, 3Berridge M.J. Nature. 1993; 361: 315-325Crossref PubMed Scopus (6196) Google Scholar, 4Noh D.-Y. Shin S.H. Rhee S.G. Biochim. Biophys. Acta. 1995; 1242: 99-114Crossref PubMed Scopus (256) Google Scholar). This reaction produces two intracellular messengers, diacylglycerol and inositol 1,4,5-trisphosphate, which mediate the activation of protein kinase C (PKC) and intracellular Ca2+ release, respectively. Furthermore, a decrease in the amount of PIP2 itself in the cell membrane is likely an important signal because the activities of several proteins are modulated by this phospholipid (5Lee S.B. Rhee S.G. Curr. Opin. Cell Biol. 1995; 7: 183-189Crossref PubMed Scopus (285) Google Scholar). PIP2 is a cofactor for phosphatidylcholine-specific phospholipase D (PLD) and a substrate for phosphoinositide 3-kinase (PI 3-kinase), both of which are also receptor-activated effector enzymes. In addition, PIP2modulates actin polymerization by interacting with various actin-binding proteins and serves as a membrane-attachment site for many signaling proteins that contain pleckstrin homology (PH) domains. Consequently, the activity of PLC is stringently regulated in cells through several distinct mechanisms that link multiple PLC isoforms to various receptors. The 10 mammalian PLC isozymes (excluding alternatively spliced forms) identified to date are all single polypeptides and can be divided into three types, β, γ, and δ, of which four PLC-β, two PLC-γ, and four PLC-δ proteins are known (1Rhee S.G. Choi K.D. J. Biol. Chem. 1992; 267: 12393-12396Abstract Full Text PDF PubMed Google Scholar, 2Cockcroft S. Thomas G.M.H. Biochem. J. 1992; 288: 1-14Crossref PubMed Scopus (371) Google Scholar, 3Berridge M.J. Nature. 1993; 361: 315-325Crossref PubMed Scopus (6196) Google Scholar, 4Noh D.-Y. Shin S.H. Rhee S.G. Biochim. Biophys. Acta. 1995; 1242: 99-114Crossref PubMed Scopus (256) Google Scholar, 5Lee S.B. Rhee S.G. Curr. Opin. Cell Biol. 1995; 7: 183-189Crossref PubMed Scopus (285) Google Scholar). The δ-type isozymes are smaller (M r 85,000) than the PLC-β and PLC-γ (M r 140,000–155,000) isoforms. Lower eukaryotes such as yeast and slime molds contain only δ-type isozymes, suggesting that β- and γ-type isoforms in higher eukaryotes evolved from the archetypal PLC-δ. Two regions of high sequence homology (40–60% identity), designated X and Y, constitute the PLC catalytic domain (1Rhee S.G. Choi K.D. J. Biol. Chem. 1992; 267: 12393-12396Abstract Full Text PDF PubMed Google Scholar, 2Cockcroft S. Thomas G.M.H. Biochem. J. 1992; 288: 1-14Crossref PubMed Scopus (371) Google Scholar, 3Berridge M.J. Nature. 1993; 361: 315-325Crossref PubMed Scopus (6196) Google Scholar, 4Noh D.-Y. Shin S.H. Rhee S.G. Biochim. Biophys. Acta. 1995; 1242: 99-114Crossref PubMed Scopus (256) Google Scholar, 5Lee S.B. Rhee S.G. Curr. Opin. Cell Biol. 1995; 7: 183-189Crossref PubMed Scopus (285) Google Scholar) (Fig.1). A PH domain is located in the NH2-terminal region, preceding the X domain, in all three types of PLC. Whereas PLC-β and PLC-δ isozymes contain a short sequence of 50–70 amino acids that separates the X and Y regions, PLC-γ isozymes have a long sequence of ∼400 amino acids that contains Src homology (SH) (two SH2 and one SH3) domains. PLC-γ isozymes contain an additional PH domain that is split by the SH domains. PH (∼100 residues), SH2 (∼100 residues), and SH3 (∼50 residues) domains are protein modules that are shared by many signaling proteins; whereas PH domains mediate interaction with the membrane surface by binding to PIP2, SH domains mediate interactions with other proteins by binding to phosphorylated tyrosine residues (SH2) or proline-rich sequences (SH3). The three-dimensional structure of a PLC-δ1 molecule lacking the PH domain has recently been determined (6Essen L.-O. Perisic O. Cheung R. Katan M. Williams R.L. Nature. 1996; 380: 595-602Crossref PubMed Scopus (519) Google Scholar). As expected, the X and Y regions are tightly assoc