MAGI-3 competes with NHERF-2 to negatively regulate LPA2 receptor signaling in colon cancer cells

• Type of Material: Article
• Authors: Sei-Jung Lee, Emory University; Stefanie L. Ritter, Emory University; Huanchun Zhang, Emory University; Hyunsuk Shim, Emory University; Randy A Hall, Emory University; Chris Yun, Emory University
• Language: English
• Date: 2011-03
• Publisher: Springer Verlag (Germany)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1053/j.gastro.2010.11.054
• Title of Journal or Parent Work: Gastroenterologe
• ISSN: 1861-9681
• Volume: 140
• Issue: 3
• Start Page: 924
• End Page: 934
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health R01DK071597 and R01DK071597-03S1 (CCY) and R01NS055179 (RAH).; National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
• Keywords: colorectal cancer; neoplasia; tumorigenesis; G-protein signaling
• Research Categories: Health Sciences, Oncology

Abstract

SUMMARY Background & Aims 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. Methods 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. Results 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. Conclusion 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.