Abstract
Lysophosphatidic acid (LPA) is a potent inducer of epithelial cell migration. The LPA receptor subptype, LPA1, is the most abundant LPA receptor in the intestinal tract; however its physiological significance remains elusive. We found that the villous height is shortened in the intestine of LPA1‐null mice (Lpar1−/−) compared with wild type (WT) mice and the rate of migration of proliferating enterocytes along the crypt‐villus axis is impaired in Lpar1−/− mice. Injection of WT mice with LPA1/LPA3 inhibitor Ki16425 decreased cell migration towards the villus tip, whereas oral administration of LPA enhanced cell migration. LPA failed to promote cell migration in Lpar1−/− mice, suggesting that LPA1 specifically regulates enterocyte migration in the mouse intestine. We further studied the mechanism of LPA1‐mediated migration in YAMC cells. Overexpression of LPA1 markedly enhanced lamellipodia formation and cell migration, whereas LPA2 had a marginal effect. The downstream signaling pathway initiated by LPA1 for YAMC cell migration involves Gαq specifically activating PLC‐β2, but not other PLC‐β isoforms. PLC‐β2 interacted with GTP‐bound Rac1 to recruit Src and Arp2/3 to the leading edge of lamellipodia, where Src and Arp2/3 interacted with FAK and cortactin, respectively. These results suggest that LPA1 is the major LPA receptor that regulates migration of proliferating enterocytes in the intestinal tract.
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