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Lysophosphatidic acid (LPA) is a lipid mediator that modulates a wide variety of cellular functions. Elevated LPA signaling has been reported in patients with colorectal cancer or inflammatory bowel diseases, and the tumorigenic role of LPA has been demonstrated in experimental models of colon cancer. However, emerging evidence indicates the importance of LPA signaling in epithelial wound healing and regulation of intestinal electrolyte transport. Here, we briefly review current knowledge of the biological roles of LPA signaling in the intestinal tract. [ABSTRACT FROM AUTHOR]

Background/Aims: Trafficking, brush border membrane (BBM) retention, and signal-specific regulation of the Na+/H+ exchanger NHE3 is regulated by the Na+/H+ Exchanger Regulatory Factor (NHERF) family of PDZ-adaptor proteins, which enable the formation of multiprotein complexes. It is unclear, however, what determines signal specificity of these NHERFs. Thus, we studied the association of NHE3, NHERF1 (EBP50), NHERF2 (E3KARP), and NHERF3 (PDZK1) with lipid rafts in murine small intestinal BBM. Methods: Detergent resistant membranes ('lipid rafts') were isolated by floatation of Triton X-incubated small intestinal BBM from a variety of knockout mouse strains in an Optiprep step gradient. Acid-activated NHE3 activity was measured fluorometrically in BCECF-loaded microdissected villi, or by assessment of CO2/HCO3- mediated increase in fluid absorption in perfused jejunal loops of anethetized mice. Results: NHE3 was found to partially associate with lipid rafts in the native BBM, and NHE3 raft association had an impact on NHE3 transport activity and regulation in vivo. NHERF1, 2 and 3 were differentially distributed to rafts and non-rafts, with NHERF2 being most raft-associated and NHERF3 entirely non-raft associated. NHERF2 expression enhanced the localization of NHE3 to membrane rafts. The use of acid sphingomyelinase-deficient mice, which have altered membrane lipid as well as lipid raft composition, allowed us to test the validity of the lipid raft concept in vivo. Conclusions: The differential association of the NHERFs with the raft-associated and the non-raft fraction of NHE3 in the brush border membrane is one component of the differential and signal-specific NHE3 regulation by the different NHERFs. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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 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 LPA2 and phospholipase C–β3. However, NHERF-2 and MAGI-3 reciprocally regulated LPA2-induced phospholipase C 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 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: 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. [ABSTRACT FROM AUTHOR]

Lysophosphatidic acid (LPA) is a mediator of multiple cellular responses. LPA mediates its effects predominantly through the G protein-coupled receptors LPA₁, LPA₂, and LPA₃. In the present work, we studied LPA₂-mediated signaling using human colon cancer cell lines, which predominantly express LPA₂. LPA₂ activated Akt and Erk1/2 in response to LPA. LPA mediated Akt activation was inhibited by pertussis toxin (PTX), whereas Erkl/2 activation was completely inhibited by a blocker of phospholipase Cβ, U-73122. LPA also induced interleukin-8 (IL-8) synthesis in the colon cancer cells by primarily activating LPA₂ receptor. We also found that LPA₂ interacts with Na+/H+ exchanger regulatory factor 2 (NHERF2). Activation of Akt and Erkl/2 was significantly attenuated by silencing of NHERF2 expression by RNA interference, suggesting a pivotal role of NHERF2 in LPA₂-mediated signaling. We found that expression of LPA₂ was elevated, whereas expression of LPA₁ downregulated in several types of cancers, including ovarian and colon cancer. We conclude that LPA₂ is the major LPA receptor in colon cancer cells and cellular signals by LPA₂ are largely mediated through its ability to interact with NHERF2. [ABSTRACT FROM AUTHOR]

The intestinal epithelium interacts dynamically with the immune system to maintain its barrier function to protect the host, while performing the physiological roles in absorption of nutrients, electrolytes, water and minerals. The importance of lysophosphatidic acid (LPA) and its receptors in the gut has been progressively appreciated. LPA signaling modulates cell proliferation, invasion, adhesion, angiogenesis, and survival that can promote cancer growth and metastasis. These effects are equally important for the maintenance of the epithelial barrier in the gut, which forms the first line of defense against the milieu of potentially pathogenic stimuli. This review focuses on the LPA-mediated signaling that potentially contributes to inflammation and tumor formation in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]