SIGNALING MECHANISMS IN GROWTH FACTOR-STIMULATED CELL MOTILITY

Most mammalian cells have the capacity to migrate, When placed into cu lture, cells will generally display a set rate of basal, unstimulated locomotion, The cells will begin to move in one direction and, after s ome time, change directions resulting in a random walk, External stimu li can influence cell motility in several ways to either enhance or re tard the rate of migration (chemokinesis), to change the average amoun t of cell migration observed before the cell turns (persistence), or t o increase the directionality of movement by limiting the number of tu rns made by the cells, Several factors have been identified that stimu late cell movement, but the signaling mechanisms that mediate this ind uced cell movement have only recently begun to be studied, In this rev iew, we discuss the signals that support the directional movement of f ibroblasts and epithelial cells in response to chemoattractant gradien ts, The work will emphasize studies carried out by our laboratory and others on the stimulation of cell motility by the PDGF, These results indicate that at least two sets of signaling molecules cooperate to re gulate cell motility in vivo. These include phospholipase e-gamma, pho sphoinositide-3' kinase and the Ras-GTPase activating protein Ras-GAP. The first set are those which bind to the intracellular domain of the receptor tyrosine kinase and bring about the phosphorylation and/or a ctivation of intracellular effecters proximal to the receptor, The sec ond is a set of downstream effecters that regulate either the rate of cell movement or the directionality of that movement depending on the cell type, These include Ras and the Ras-related GTPase Rac along with free phosphoinositides and calcium ions that regulate the actin polym erization machinery, Signals that mediate nuclear changes leading to c ell proliferation, such as elements of the MAP kinase pathway, do not appear to play a role in PDGF-stimulated cell migration, Current work thus suggests that a coordinated spatial regulation of signaling eleme nts that interact with the cell membrane and cytoskeleton but not nece ssarily with nuclear elements is the controlling mediator of direction al cell motility.