Glycogen synthase kinase-3 acts upstream of ADP-ribosylation factor 6 and Rac1 to regulate epithelial cell migration

Experimental Cell Research
Rizwan FarooquiGabriel Fenteany

Abstract

Cell sheet movement during epithelial wound closure is a complex process involving collective cell migration. We have found that glycogen synthase kinase-3 (GSK-3) activity is required for membrane protrusion and crawling of cells at the wound edge and those behind it in wounded Madin-Darby canine kidney (MDCK) epithelial cell monolayers. RNA interference-based silencing of GSK-3alpha and GSK-3beta expression also results in slowed cell sheet migration, with the effect being more pronounced with knockdown of GSK-3beta. Both GSK-3alpha and GSK-3beta are in activated states during the most active phase of cell migration. In addition to having a positive control or permissive, rather than negative, function in MDCK cell migration, GSK-3 appears to act upstream of the small GTPases ADP-ribosylation factor 6 (ARF6) and Rac1. Expression of constitutively active ARF6 restores a protrusive, migratory phenotype in cells treated with GSK-3 inhibitors. It does not, however, restore to normal levels the directional polarization of cells behind the wound edge toward the wound area, implying the existence of a separate ARF6-independent branch of the GSK-3 pathway that regulates proper wound-directed polarization of these cells. Finally, inhi...Continue Reading

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