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

Gastroenterology. 2011 Mar;140(3):924-34. doi: 10.1053/j.gastro.2010.11.054. Epub 2010 Dec 4.


Background & aims: Lysophosphatidic acid (LPA) is a potent inducer of colon cancer and LPA receptor type 2 (LPA(2)) is overexpressed in colon tumors. LPA(2) 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 LPA(2)-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 nuclear factor-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 LPA(2) and phospholipase C-β3. However, NHERF-2 and MAGI-3 reciprocally regulated LPA(2)-induced phospholipase C activity. MAGI-3 increased the interaction of LPA(2) with Gα(12), whereas NHERF-2 preferentially promoted interaction between LPA(2) and Gα(q). MAGI-3 decreased the tumorigenic capacity of LPA(2) by attenuating the activities of nuclear factor-κB and c-Jun N-terminal kinase. MAGI-3 and NHERF-2 were expressed differentially in colon adenocarcinomas, consistent with their opposing effects.

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

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Adenomatous Polyposis Coli / genetics
  • Adenomatous Polyposis Coli / metabolism
  • Animals
  • Cell Movement
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Disease Models, Animal
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Genes, APC
  • HCT116 Cells
  • Humans
  • Inositol Phosphates / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lysophospholipids / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Phospholipase C beta / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • RNA Interference
  • Receptors, Lysophosphatidic Acid / genetics
  • Receptors, Lysophosphatidic Acid / metabolism*
  • Signal Transduction*
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / metabolism*
  • Time Factors
  • Tissue Array Analysis
  • Transfection


  • Inositol Phosphates
  • Lysophospholipids
  • MAGI3 protein, human
  • Membrane Proteins
  • NF-kappa B
  • Phosphoproteins
  • Receptors, Lysophosphatidic Acid
  • Sodium-Hydrogen Exchangers
  • sodium-hydrogen exchanger regulatory factor
  • JNK Mitogen-Activated Protein Kinases
  • PLCB3 protein, human
  • Phospholipase C beta
  • GTP-Binding Protein alpha Subunits, G12-G13
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • lysophosphatidic acid