SUPPRESSION OF RUFFLING BY THE EGF RECEPTOR IN CHEMOTACTIC CELLS

To clarify the relationship between ruffling and lamellipod extension in growth factor-stimulated chemotactic responses, we utilized cell li nes derived from the rat 13762 NF mammary adenocarcinoma. Non-metastat ic MTC cells expressing the human EGF receptor (termed MTC HER cells) demonstrated chemotactic responses to TGF-alpha, an EGF receptor ligan d typically present in mammary tissue. In microchemotaxis chambers, pe ak chemotactic responses occurred in response to 5 nM TGF-alpha. MTC H ER cells showed dramatic ruffling edges in the absence of external sti muli, and addition of 5 nM TGF-alpha led to a transient reduction in r uffling concomitant with lamellipod extension. Lamellipod extension co rrelated with an overall increase in actin polymerization. These respo nses were blocked by the PI 3 kinase inhibitor wortmannin but not by t he MAP kinase inhibitors PD98059 and SB203580. We conclude that the in itial chemotactic response to TGF-alpha involves lamellipod extension and that ruffling reflects a dynamic turnover of lamellipodia that is arrested during lamellipod extension. By regulating the dissolution of ruffles and extension of lamellipods, a chemotactic response can be a chieved, which may contribute to the metastatic process. (C) 1998 Acad emic Press.