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Molecular and Cellular Biology, June 2004, p. 5069-5079, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.5069-5079.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

NHERF2 Specifically Interacts with LPA2 Receptor and Defines the Specificity and Efficiency of Receptor-Mediated Phospholipase C-ß3 Activation

Yong-Seok Oh,1 Nam Won Jo,1 Jung Woong Choi,1 Hyeon Soo Kim,1 Sang-Won Seo,1 Kyung-Ok Kang,1 Jong-Ik Hwang,1 Kyun Heo,1 Sun-Hee Kim,1 Yun-Hee Kim,1 In-Hoo Kim,2 Jae Ho Kim,3 Yoshiko Banno,4 Sung Ho Ryu,1 and Pann-Ghill Suh1*

Department of Life Science, Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyung-Buk 790-784,1 Division of Basic Sciences, National Cancer Center, Ilsan-Gu, Goyang-Si, Gyeonggi-do 411-764,2 Department of Physiology, College of Medicine, Pusan National University, Suh-Gu, Busan 620-739, Republic of Korea,3 Department of Biochemistry and Internal Medicine, Gifu University School of Medicine, Gifu 500-8705, Japan4

Received 12 September 2003/ Returned for modification 18 November 2003/ Accepted 30 January 2004

Lysophosphatidic acid (LPA) activates a family of cognate G protein-coupled receptors and is involved in various pathophysiological processes. However, it is not clearly understood how these LPA receptors are specifically coupled to their downstream signaling molecules. This study found that LPA2, but not the other LPA receptor isoforms, specifically interacts with Na+/H+ exchanger regulatory factor2 (NHERF2). In addition, the interaction between them requires the C-terminal PDZ domain-binding motif of LPA2 and the second PDZ domain of NHERF2. Moreover, the stable expression of NHERF2 potentiated LPA-induced phospholipase C-ß (PLC-ß) activation, which was markedly attenuated by either a mutation in the PDZ-binding motif of LPA2 or by the gene silencing of NHERF2. Using its second PDZ domain, NHERF2 was found to indirectly link LPA2 to PLC-ß3 to form a complex, and the other PLC-ß isozymes were not included in the protein complex. Consistently, LPA2-mediated PLC-ß activation was specifically inhibited by the gene silencing of PLC-ß3. In addition, NHERF2 increases LPA-induced ERK activation, which is followed by cyclooxygenase-2 induction via a PLC-dependent pathway. Overall, the results suggest that a ternary complex composed of LPA2, NHERF2, and PLC-ß3 may play a key role in the LPA2-mediated PLC-ß signaling pathway.

* Corresponding author. Mailing address: Department of Life Science, Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea. Phone: 82-54-279-2293. Fax: 82-54-279-8379. E-mail: pgs{at}postech.ac.kr.

Molecular and Cellular Biology, June 2004, p. 5069-5079, Vol. 24, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.11.5069-5079.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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