To date, 12 secreted phospholipases A2 (sPLA2s) have been identified in the mouse species and divided into three structural collections (I/II/V/X, III, and XII). On the basis of their different molecular properties and tissue distributions, each sPLA2 is likely to exert distinct functions by acting as an enzyme or ligand for specific soluble proteins or receptors, among which the M-type receptor is the best-characterized target. Here, we present the properties of binding of the full set of mouse sPLA2s to the mouse M-type receptor. All enzymes have been produced in Escherichia coli or insect cells, and their properties of binding to the cloned and native M-type receptor have been determined. sPLA2s IB, IIA, IIE, IIF, and X are high-affinity ligands (K0.5 = 0.3-3 nM); sPLA2s IIC and V are low-affinity ligands (K0.5 = 30-75 nM), and sPLA2s IID, III, XIIA, and XIIB bind only very weakly or do not bind to the M-type receptor (K0.5 > 100 nM). Three exogenous parvoviral group XIII PLA2s and two fungal group XIV sPLA2s do not bind to the receptor. Together, these results indicate that the mouse M-type receptor is selective for only a subset of mouse sPLA2s from the group I/II/V/X structural collection. Binding of mouse sPLA2s to a recombinant soluble mouse M-type receptor leads in all cases to inhibition of enzymatic activity, and the extent of deglycosylation of the receptor decreases yet does not abolish sPLA2 binding. The physiological meaning of binding of sPLA2 to the M-type receptor is discussed on the basis of our current knowledge of sPLA2 functions.

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Among mammalian secreted phospholipases A 2 (sPLA 2 s), the group X enzyme has the most potent hydrolyzing capacity toward phosphatidylcholine, the major phospholipid of cell membrane and lipoproteins. This enzyme has recently been implicated in chronic inflammatory diseases such as atherosclerosis and asthma and may also play a role in colon tumorigenesis. We show here that group X sPLA 2 [mouse (m)GX] is one of the most highly expressed PLA 2 in the mouse colon and that recombinant mouse and human enzymes stimulate proliferation and mitogen-activated protein kinase activation of various colon cell lines, including Colon-26 cancer cells. Among various recombinant sPLA 2 s, mGX is the most potent enzyme to stimulate cell proliferation. Based on the use of sPLA 2 inhibitors, catalytic site mutants, and small interfering RNA silencing of cytosolic PLA 2 ␣ and M-type sPLA 2 receptor, we demonstrate that mGX promotes cell proliferation independently of the receptor and via its intrinsic catalytic activity and production of free arachidonic acid and lysophospholipids, which are mitogenic by themselves. mGX can also elicit the production of large amounts of prostaglandin E 2 and other eicosanoids from Colon-26 cells, but these lipid mediators do not play a role in mGX-induced cell proliferation because inhibitors of cyclooxygenases and lipoxygenases do not prevent sPLA 2 mitogenic effects. Together, our results indicate that group X sPLA 2 may play an important role in colon tumorigenesis by promoting cancer cell proliferation and releasing various lipid mediators involved in other key events in cancer progression.Phospholipases A 2 (PLA 2 s) catalyze the hydrolysis of the sn-2 ester bond of glycerophospholipids to generate free fatty acids and lysophospholipids (Schaloske and Dennis, 2006;Lambeau and Gelb, 2008). Over the past few years, it has been realized that PLA 2 s constitute a superfamily of enzymes comprising several intracellular enzymes and secreted PLA 2 s (sPLA 2 s).The group IVA cytosolic PLA 2 (cPLA 2 ␣) is the best known intracellular PLA 2 , and it clearly plays an important, yet not exclusive role in the release of arachidonic acid (AA) and subsequent production of eicosanoids in various biological settings (Kita et al., 2006). In contrast, the biological functions of the different sPLA 2 s are slowly being unraveled. sPLA 2 s have been implicated in lipid digestion and obesity; activation of immune cells; asthma; atherosclerosis; acute respiratory distress syndrome; and host defense against bac-