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Author Notes:

Address correspondence to: C. Chris Yun, Division of Digestive Diseases, Emory University School of Medicine, Whitehead Bldg. Room 201, 615 Michael St. Atlanta, GA 30322. Tel) 404-712-2865, ccyun@emory.edu

S.L.: Study concept and design, acquisition of data, analysis and interpretation of data, statistic analysis, drafting of the manuscript

S.L.R.: Study concept and design, acquisition of data, analysis and interpretation of data, statistic analysis, drafting of the manuscript

H.Z.: acquisition of data, analysis and interpretation of data

H.S.: Study concept and design, study supervision

R.A.H.: Study concept and design, analysis and interpretation of data, drafting of the manuscript, funding, study supervision

C.C.Y.: Study concept and design, analysis and interpretation of data, drafting of the manuscript, funding, study supervision

We thank Dr. Pann-Ghill Suh for PLC-β clones.

We acknowledge the Emory Digestive Disease Research Development Center (supported by DK064399) for HCT116 and SW480 cells.

No conflict of interest exists.

Subject:

Research Funding:

National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK

This work was supported by grants from the National Institutes of Health R01DK071597 and R01DK071597-03S1 (CCY) and R01NS055179 (RAH).

Keywords:

  • G-protein signaling
  • colorectal cancer
  • neoplasia
  • tumorigenesis

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

Tools:

Journal Title:

Gastroenterologe

Volume:

Volume 140, Number 3

Publisher:

, Pages 924-934

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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