NHERF2 specifically interacts with LPA2 receptor and defines the specificity and efficiency of receptor-mediated phospholipase C-beta3 activation.
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 LPA(2), 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 LPA(2) and the second PDZ domain of NHERF2. Moreover, the stable expression of NHERF2 potentiated LPA-induced phospholipase C-beta (PLC-beta) activation, which was markedly attenuated by either a mutation in the PDZ-binding motif of LPA(2) or by the gene silencing of NHERF2. Using its second PDZ domain, NHERF2 was found to indirectly link LPA(2) to PLC-beta3 to form a complex, and the other PLC-beta isozymes were not included in the protein complex. Consistently, LPA(2)-mediated PLC-beta activation was specifically inhibited by the gene silencing of PLC-beta3. 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 LPA(2), NHERF2, and PLC-beta3 may play a key role in the LPA(2)-mediated PLC-beta signaling pathway.
Oh
Yong-Seok
YS
Department of Life Science, Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea.
Jo
Nam Won
NW
Choi
Jung Woong
JW
Kim
Hyeon Soo
HS
Seo
Sang-Won
SW
Kang
Kyung-Ok
KO
Hwang
Jong-Ik
JI
Heo
Kyun
K
Kim
Sun-Hee
SH
Kim
Yun-Hee
YH
Kim
In-Hoo
IH
Kim
Jae Ho
JH
Banno
Yoshiko
Y
Ryu
Sung Ho
SH
Suh
Pann-Ghill
PG
D000818:Animals; D019556:COS Cells; D051546:Cyclooxygenase 2; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D054799:Phospholipase C beta; D010750:Phosphoproteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid; D017923:Sodium-Hydrogen Exchangers; D013379:Substrate Specificity; D010738:Type C Phospholipases / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; C518039:PLCB3 protein, human; D054799:Phospholipase C beta