The Phospholipase C Isozymes and Their Regulation

Abstract

The physiological effects of many extracellular neurotransmitters, hormones, growth factors, and other stimuli are mediated by receptor-promoted activation of phospholipase C (PLC) and consequential activation of inositol lipid signaling pathways. These signaling responses include the classically described conversion of phosphatidylinositol(4,5)P2 to the Ca2+-mobilizing second messenger inositol(1,4,5)P3 and the protein kinase C-activating second messenger diacylglycerol as well as alterations in membrane association or activity of many proteins that harbor phosphoinositide binding domains. The 13 mammalian PLCs elaborate a minimal catalytic core typified by PLC-δ to confer multiple modes of regulation of lipase activity. PLC-β isozymes are activated by Gαq- and Gβγ-subunits of heterotrimeric G proteins, and activation of PLC-γ isozymes occurs through phosphorylation promoted by receptor and non-receptor tyrosine kinases. PLC-ε and certain members of the PLC-β and PLC-γ subclasses of isozymes are activated by direct binding of small G proteins of the Ras, Rho, and Rac subfamilies of GTPases. Recent high resolution three dimensional structures together with biochemical studies have illustrated that the X/Y linker region of the catalytic core mediates autoinhibition of most if not all PLC isozymes. Activation occurs as a consequence of removal of this autoinhibition.

Structural Insights into Phospholipase C-β Function

“…There are six subfamilies of PLC in higher eukaryotes (Gresset et al, 2012;Kadamur and Ross, 2013). Of these, the PLCb subfamily is among the most intensively studied.…”

“…GPCRmediated activation of PLCb also occurs through release of the Gbg heterodimer, which is thought to be mediated by activation of G i -coupled GPCRs (Camps et al, 1992;Katz et al, 1992;Wu et al, 1998;Xie et al, 1999). Members of the Rho family of small molecular weight G proteins, such as the Rac isoforms, also directly bind and activate PLCb, linking PLCb activity to GPCR-independent signaling cascades (Gresset et al, 2012;Kadamur and Ross, 2013). It is also increasingly recognized that the membrane itself plays a role in the regulation of PLCb, as may interactions with scaffolding proteins (Cartier et al, 2011;Grubb et al, 2011Grubb et al, , 2012Sun et al, 2013).…”

Dysfunction of phospholipase Cγ in immune disorders and cancer

“…Different aspects of PLC-mediated signalling have been covered in a number of excellent reviews that focus, for example, on the catalytic mechanism [7], regulatory interactions and physiological roles of PLC families [1][2][3][4][5] or on structural and mechanistic aspects of regulation [8][9][10]. In this review, we highlight recent experimental evidence related to the dysfunction of PLCγ enzymes and links to disease, based on genetic and genomic analysis of animal models and patients; we further discuss the molecular mechanisms that underpin dysfunction.…”

Role of bioactive lipid mediators in obese adipose tissue inflammation and endocrine dysfunction

“…This synthetic pathway can be reversed, and by the action of lipases (ATGL or HSL) TAG is hydrolyzed to DAG. Moreover, phospholipase C (PLC) can directly release DAG from phospholipids, by a hydrolytical reaction between the phosphate and the glycerol backbone (Gresset et al, 2012). All these reactions give rise to the 1,2 or the 2,3 DAG isoform; however, in some edible oils DAG can be found as a minor constituent in its 1,3 isoform, which is produced during high temperature, manufacturing processes (Flickinger and Matsuo, 2003).…”

“…PLC can generate DAG from phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. This reaction releases inositol triphosphate (IP3) to the cytosol (Gresset et al, 2012), which stimulates calcium release. On the other hand, DAG is hydrophobic and remains in the membrane, acting as a signal messenger for activation of protein kinase C (PKC), and facilitates its translocation to the cellular membrane.…”