Autotaxin and lysophosphatidic acid stimulate intestinal cell motility by redistribution of the actin modifying protein villin to the developing lamellipodia.
Autotaxin (ATX) is a potent tumor cell motogen that can produce lysophosphatidic acid (LPA) from lysophosphatidylcholine. LPA is a lipid mediator that has also been shown to modulate tumor cell invasion. Autotaxin mRNA is expressed at significant levels in the intestine. Likewise, LPA2 receptor levels have been shown to be elevated in colon cancers. The molecular mechanism of ATX/LPA-induced increase in intestinal cell migration however, remains poorly understood. Villin is an intestinal and renal epithelial cell specific actin regulatory protein that modifies epithelial cell migration. In this study we demonstrate that both Caco-2 (endogenous villin) and MDCK (exogenous villin) cells, which express primarily LPA2 receptors, show enhanced cell migration in response to ATX/LPA. ATX and LPA treatment results in the rapid formation of lamellipodia and redistribution of villin to these cell surface structures, suggesting a role for villin in regulating this initial event of cell locomotion. The LPA-induced increase in cell migration required activation of c-src kinase and downstream tyrosine phosphorylation of villin by c-src kinase. LPA stimulated cell motility was determined to be insensitive to pertussis toxin, but was regulated by activation of PLC-gamma 1. Together, our results show that in epithelial cells ATX and LPA act as strong stimulators of cell migration by recruiting PLC-gamma 1 and villin, both of which participate in the initiation of protrusion.
Department of Physiology, University of Tennessee Health Science Center Memphis, TN 38163, USA. skhurana@utmem.edu <skhurana@utmem.edu>
Seema
S
Khurana
Alok
A
Tomar
Sudeep P
SP
George
Yaohong
Y
Wang
Mohammad Rizwan
MR
Siddiqui
Huazhang
H
Guo
Gabor
G
Tigyi
Sijo
S
Mathew
D000199:Actins / Q000378:metabolism; D000818:Animals; D018938:Caco-2 Cells; D002277:Carcinoma / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004285:Dogs; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology / Q000502:physiology*; D008840:Microfilament Proteins / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000494:pharmacology / Q000502:physiology*; D043264:Phosphodiesterase I / Q000494:pharmacology / Q000502:physiology*; D051966:Phospholipase C gamma / Q000187:drug effects / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D011755:Pyrophosphatases / Q000494:pharmacology / Q000502:physiology*; D049368:Receptors, Lysophosphatidic Acid / Q000187:drug effects / Q000378:metabolism; D019061:src-Family Kinases / Q000187:drug effects / Q000378:metabolism; D000099189:Lysophospholipase D
D000199:Actins; D008246:Lysophospholipids; D008840:Microfilament Proteins; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D051966:Phospholipase C gamma; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D049368:Receptors, Lysophosphatidic Acid; D019061:src-Family Kinases; D000099189:Lysophospholipase D; C026615:villin; C032881:lysophosphatidic acid