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J. Biol. Chem., Vol. 280, Issue 26, 24576-24583, July 1, 2005

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Identification of Novel Cytosolic Phospholipase A₂s, Murine cPLA₂, , and , Which Form a Gene Cluster with cPLA₂^*

Takayo Ohto, Naonori Uozumi, Tetsuya Hirabayashi, and Takao Shimizu¶

From the Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan and the Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Science, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan

Phospholipase A₂ hydrolyzes the sn-2 ester bond of glycerophospholipids that produce free fatty acids and lysophospholipids. Cytosolic phospholipase A₂s (cPLA₂, group IV) are a subgroup of enzymes that act on the intracellular phospholipid membrane. The best investigated cPLA₂ (group IVA) is a key enzyme for lipid mediator production in vivo. Here we report cloning and characterization of novel murine cPLA₂s: cPLA₂ (group IVD), cPLA₂ (group IVE), and cPLA₂ (group IVF), that form a gene cluster with cPLA₂ (group IVB). The deduced amino acid sequences of cPLA₂, , and demonstrated a conserved domain structure of cPLA₂, i.e. one C2 domain and one lipase domain. The potential catalytic dyad, Ser and Asp, was conserved for these newly cloned cPLA₂s along with relatively high conservation for the surrounding residues. Transcripts of murine cPLA₂, , and appeared to be enriched in certain organs rather than ubiquitous distribution. Major Northern signals for cPLA₂ were detected in placenta, cPLA₂ in thyroid, heart, and skeletal muscle, and cPLA₂ in thyroid. Recombinant proteins expressed in human embryonic kidney 293 cells demonstrated molecular sizes of about 100 kDa by Western blotting and exhibited Ca²⁺-dependent PLA₂ activities on 1-palmitoyl-2-[¹⁴C]arachidonoyl-phosphatidylcholine substrate. In contrast to cPLA₂, cPLA₂ preferred phosphatidylethanolamine to phosphatidylcholine. Intracellular localization was visualized by green fluorescent-tagged proteins. Each molecule showed specific localization, and cPLA₂ translocated from the cytosol to the perinuclear region by calcium-ionophore stimulation. We thus discovered these functional novel cPLA₂ genes, which cluster on murine chromosome 2E5.

Received for publication, December 6, 2004 , and in revised form, April 28, 2005.

^* This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to T. S. and N. U.), and a grant from the ONO Medical Research Foundation (to N. U.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables I and II.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB195276 for cPLA₂, AB195277 for cPLA₂, and AB195278 for cPLA₂.

^¶ To whom correspondence should be addressed. Tel.: 81-3-5802-2925; Fax: 81-3-3813-8732; E-mail: tshimizu{at}m.u-tokyo.ac.jp.

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