THE CHEMOTACTIC RESPONSE TO PDGF-BB - EVIDENCE OF A ROLE FOR RAS

The PDGF receptor-beta mediates both mitogenic and chemotactic respons es to PDGF-BB. Although the role of Ras in tyrosine kinase-mediated mi togenesis has been characterized extensively, its role in PDGF-stimula ted chemotaxis has not been defined. Using cells expressing a dominant -negative ras, we find that Ras inhibition suppresses migration toward PDGF-BB. Overexpression of either Ras-GTPase activating protein (Ras- GAP) or a Ras guanine releasing factor (GRF) also inhibited PDGF-stimu lated chemotaxis. In addition, cells producing excess constitutively a ctive Ras failed to migrate toward PDGF-BB, consistent with the observ ation that either excess ligand or excess signaling intermediate can s uppress the chemotactic response. These results suggest that Ras can f unction in normal cells to support chemotaxis toward PDGF-BB and that either too little or too much Ras activity can abrogate the chemotacti c response. In contrast to Ras overexpression, cells producing excess constitutively active Raf, a downstream effector of Ras, did migrate t oward PDGF-BB. Cells expressing dominant-negative Ras were able to mig rate toward soluble fibronectin demonstrating that these cells retaine d the ability to migrate. These results suggest that Ras is an interme diate in PDGF-stimulated chemotaxis but may not be required for fibron ectin-stimulated cell motility.