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Journal of Lipid Research, Vol. 50, 685-693, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

The tumor suppressor gene H-Rev107 functions as a novel Ca²⁺-independent cytosolic phospholipase A_1/2 of the thiol hydrolase type

Toru Uyama^*, Jun Morishita^*, Xing-Hua Jin^*,, Yasuo Okamoto^*,, Kazuhito Tsuboi^* and Natsuo Ueda^1,*

^* Department of Biochemistry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan
Department of Chemistry, Qiqihar Medical University, Qiqihar 161006, China
Department of Physiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8640, Japan

This work was supported by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and Japan Society for the Promotion of Science, grants-in-aid from Medical Institution Union Foundation and the Japan Foundation for Applied Enzymology, Kagawa University Specially Promoted Research Fund 2008, and the Fund for Kagawa University Young Scientists 2008.

Published, JLR Papers in Press, December 1, 2008.

¹ To whom correspondence should be addressed. e-mail: nueda{at}med.kagawa-u.ac.jp

H-Rev107 is a protein that was previously cloned as a negative regulator of proto-oncogene Ras and classified as a class II tumor suppressor. Its structural similarity to lecithin retinol acyltransferase and Ca²⁺-independent phosphatidylethanolamine (PE) N-acyltransferase led us to analyze H-Rev107 as an enzyme involved in phospholipid metabolism. Here, we show that recombinant H-Rev107s from rat, human, and mouse possess phospholipase (PL) A₁ or A₂ activity toward phosphatidylcholine (PC). Further examination with purified recombinant protein revealed that H-Rev107 functions as a cytosolic Ca²⁺-independent PLA_1/2 for PC and PE with higher PLA₁ activity than PLA₂ activity. Dithiothreitol and iodoacetic acid exhibited stimulatory and inhibitory effects, respectively. Histidine-21 and cysteine-111 of rat H-Rev107 were presumed to form a catalytic dyad based on database analysis, and their single mutants were totally inactive. These results suggested that H-Rev107 is a hydrolase of the thiol type. The N-terminal proline-rich and C-terminal hydrophobic domains of H-Rev107 were earlier reported to be responsible for the regulation of cell proliferation. Analysis of deletion mutants indicated that these domains are also catalytically essential, suggesting relevance of the catalytic activity to the anti-proliferative activity.

Supplementary key words N-acyltransferase • glycerophospholipid • lecithin retinol acyltransferase

Abbreviations: BEL, bromoenol lactone; iNAT, Ca²⁺-independent N-acyltransferase; iPLA₂, Ca²⁺-independent PLA₂; LRAT, lecithin retinol acyltransferase; MAFP, methyl arachidonyl fluorophosphonate; NAPE, N-acylphosphatidylethanolamine; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PL, phospholipase

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