NHERF2 Specifically Interacts with LPA2 Receptor and Defines the Specificity and Efficiency of Receptor-Mediated Phospholipase C-β3 Activation
Open Access
- 1 June 2004
- journal article
- research article
- Published by Taylor & Francis in Molecular and Cellular Biology
- Vol. 24 (11) , 5069-5079
- https://doi.org/10.1128/mcb.24.11.5069-5079.2004
Abstract
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-β (PLC-β) 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-β3 to form a complex, and the other PLC-β isozymes were not included in the protein complex. Consistently, LPA2-mediated PLC-β activation was specifically inhibited by the gene silencing of PLC-β3. 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-β3 may play a key role in the LPA2-mediated PLC-β signaling pathway.Keywords
This publication has 47 references indexed in Scilit:
- Ca2+-dependent Inhibition of Na+/H+ Exchanger 3 (NHE3) Requires an NHE3-E3KARP-α-Actinin-4 Complex for Oligomerization and EndocytosisPublished by Elsevier ,2002
- Plasma Membrane Ca2+ ATPase Isoform 2b Interacts Preferentially with Na+/H+ Exchanger Regulatory Factor 2 in Apical Plasma MembranesPublished by Elsevier ,2002
- Evidence for Selective Coupling of α1-Adrenergic Receptors to Phospholipase C-β1 in Rat Neonatal CardiomyocytesPublished by Elsevier ,2001
- P2Y2 Purinergic and M3 Muscarinic Acetylcholine Receptors Activate Different Phospholipase C-β Isoforms That Are Uniquely Susceptible to Protein Kinase C-dependent Phosphorylation and InactivationPublished by Elsevier ,2000
- ERM-Merlin and EBP50 Protein Families in Plasma Membrane Organization and FunctionAnnual Review of Cell and Developmental Biology, 2000
- Lysophosphatidic acid (LPA) receptors of the EDG family are differentially activated by LPA speciesFEBS Letters, 2000
- Carbachol-stimulated Transactivation of Epidermal Growth Factor Receptor and Mitogen-activated Protein Kinase in T84 Cells Is Mediated by Intracellular Ca2+, PYK-2, and p60Journal of Biological Chemistry, 2000
- Genomic Characterization of the Lysophosphatidic Acid Receptor Gene, lpA2/Edg4, and Identification of a Frameshift Mutation in a Previously Characterized cDNAGenomics, 2000
- Suppression of Phospholipase C β, γ, and δ Families Alters Cell Growth and Phosphatidylinositol 4,5-Bisphosphate LevelsBiochemistry, 1997
- Site-directed mutagenesis by overlap extension using the polymerase chain reactionGene, 1989