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A. & Poplack, D.G.) 6th edn 279–255 (Lippincott Williams & Wilkins, 2011). 63. Alcorn, J. & McNamara, P. J. Phamacokinetics in the newborn. Adv Drug. Delivery Rev. 55, 667–686 (2003). 64. de Wildt, S. N., Johnson, T. N. & Choonara, I. The effect of age on drug metabolism. Paediatric Perinatal Drug Ther. 5, 101–106 (2003). 65. Bissinger, R. L. Renal physiology part 1: structure and function. Neonatal Netw. 14, 9–20 (1995). Competing interests statement The authors declare no competing financial interests. FURTHER INFORMATION Children’s Oncology Group: http://childrensoncologygroup.org/ ALL LINKS ARE ACTIVE IN THE ONLINE PDF Phospholipids, including phosphatidyl‑ choline, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and phosphatidylinositol, are major struc‑ tural components of the cell membrane 1,2 . Furthermore, phospholipids can be broken down into bioactive lipid mediators by phospholipases, such as phospholipase A (PLA), PLC and PLD, through hydrolysis 3,4 . Through intercellular and intracellular sig‑ nalling, lipid mediators regulate a variety of cellular physiological and pathophysiological OPINION Phospholipase signalling networks in cancer Jong Bae Park, Chang Sup Lee, Jin-Hyeok Jang, Jaewang Ghim, Youn-Jae Kim, Sungyoung You, Daehee Hwang, Pann-Ghill Suh and Sung Ho Ryu Abstract | Phospholipases (PLC, PLD and PLA) are essential mediators of intracellular and intercellular signalling. They can function as phospholipid-hydro- lysing enzymes that can generate many bioactive lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid and arachidonic acid. Lipid mediators generated by phospholipases regulate multiple cellular processes that can promote tumorigenesis, including proliferation, migration, invasion and angiogenesis. Although many individual phospholipases have been extensively studied, how phospholipases regulate diverse cancer-associated cellular processes and the interplay between different phospholipases have yet to be fully elucidated. A thorough understanding of the cancer-associated signalling networks of phospholipases is necessary to determine whether these enzymes can be targeted therapeutically. functions, including proliferation, survival, migration, vesicle trafficking, tumorigenesis, metastasis and inflammation 5,6 . Until recently, research on phospho‑ lipases has been carried out in a subfamily‑ specific manner. Each phospholipase regulates specific signalling pathways, but shares common signalling molecules with other members of its subfamily as upstream regulators or downstream effectors. Recent findings have indicated that phospholipases crosstalk with one another, influencing cell fate by integrating and fine‑tuning intra‑ cellular signals 3–5 . To understand these complex signalling systems in the micro‑ environments of tumours, as well as in individual tumour cells, systematic analyses of phospholipase functions are required. In this Opinion article, we summarize our current understanding of the various roles of phospholipases in tumour progression, with a focus on the signalling networks of phospholipases. We also discuss potential strategies for treating cancer through the disruption of these networks. Characteristics of phospholipases Phospholipases can be categorized into three major classes, PLA (consisting of A1 and A2), PLC and PLD, which are differentiated by the type of reaction that they catalyse 7,8 (FIG. 1a). For example, PLA1 and PLA2 target the sn‑1 and sn‑2 positions of the glycerol moieties of phospholipids to generate free fatty acids and 2‑acyl lysophospholipid or 1‑acyl lysophospholipid, respectively. Phosphatidylinositol‑hydrolysing PLC cleaves the bond between the glycerol and phosphate moieties to generate the phos‑ phorylated base (inositol‑1,4,5‑trisphos‑ phate (IP 3 ; also known as Ins(1,4,5)P 3 )) and diacylglycerol (DAG). Phosphatidylcholine‑ hydrolysing PLD hydrolyses the phospho‑ diester bond between glycerol phosphate and the substituent to generate a free base (choline) and phosphatidic acid. Each class of phospholipase is composed of many isotypes with distinct functions, domains and regulatory mechanisms 9–12 (FIG. 1b–d). Cytosolic PLA2 (cPLA2s) and PLCδ1 have a calcium‑binding C2 domain, which is required for activating these enzymes; in PLCδ1 this may occur through an enzyme–phosphatidylserine–calcium ternary complex 11,13 . Unlike the C2 domain of PLCδ1, PLCβ1 and PLCβ2 C2 domains do not interact with lipid membranes in the presence of calcium but instead associ‑ ate with GTP‑bound Gα q , which leads to the activation of native enzymes (PLCβ1 and PLCβ2) 14 . Additionally, PLC (with the PERSPECTIVES 782 | NOVEMBER 2012 | VOLUME 12 www.nature.com/reviews/cancer © 2012 Macmillan Publishers Limited. All rights reserved