Lysophosphatidic acid (LPA) is a potent inducer of colon cancer and LPA receptor type 2 (LPA2) is overexpressed in colon tumors. LPA2 interacts with membrane-associated guanylate kinase with inverted orientation-3 (MAGI-3) and the Na+/H+ exchanger regulatory factor 2 (NHERF-2), but the biological effects of these interactions are unknown. We investigated the roles of MAGI-3 and NHERF-2 in LPA2- mediated signaling in human colon cancer cells.

We overexpressed or knocked down MAGI-3 in HCT116 and SW480 cells. The effects of MAGI-3 and NHERF-2 in LPA-induced cell migration, invasion, inositol phosphate generation, and NF-κB activation were determined. Expression of MAGI-3 and NHERF-2 in human colon tumor tissues was analyzed using tissue microarray analysis.

NHERF-2 promoted migration and invasion of colon cancer cells, whereas MAGI-3 inhibited these processes. MAGI-3 competed with NHERF-2 for binding to LPA2 and phospholipase C (PLC)-β3. However, NHERF-2 and MAGI-3 reciprocally regulated LPA2-induced PLC activity. MAGI-3 increased the interaction of LPA2 with Gα12, whereas NHERF-2 preferentially promoted interaction between LPA2 and Gαq. MAGI-3 decreased the tumorigenic capacity of LPA2 by attenuating the activities of NF-κB and c-Jun N-terminal kinase. MAGI-3 and NHERF-2 were differentially expressed in colon adenocarcinomas, consistent with their opposing effects.

LPA2 is dynamically regulated by 2 distinct PDZ proteins via modulation of G protein coupling and receptor signaling. MAGI-3 is a negative regulator of LPA2 signaling.

Copyright © 2010. Published by Elsevier Inc.

PMID: 21134377 [PubMed - as supplied by publisher] Source: National Library of Medicine.