A differential role of extracellular signal-regulated kinase in stimulatedPC12 pheochromocytoma cell movement

Rat pheochromocytoma PC12 cells have been widely used as a cell system for study of growth factor-stimulated cell functions. We report here that nerve growth factor (NGF) stimulated both chemotaxis (directional migration) and chemokinesis (random migration) of PC12 cells. Treatment with a MEK1/2-spe cific inhibitor (PD98059) or expression of a dominant negative variant of R as differentially inhibited NGF-stimulated chemotaxis but not chemokinesis of PC12 cells. Priming of PC12 cells with NGF resulted in reduced extracell ular signal-regulated kinase (ERK) activation and loss of chemotactic, but not chemokinetic, response. In addition, NGF stimulation of ERK is known to involve an early transient phase of activation followed by a late sustaine d phase of activation; in contrast, epidermal growth factor (EGF) elicits o nly early transient ERK activation. We observed that like NGF, EGF also sti mulated both chemotaxis and chemokinesis, and treatment with PD98059 abolis hed the EGF-stimulated chemotaxis. Therefore, the early transient phase of ERK activation functioned in signaling chemotaxis; the late sustained phase of ERK activation did not seem to have an essential role. In addition, our results suggested that chemotactic signaling required a threshold level of ERK activation; at below threshold level of ERK activation, chemotaxis wou ld not occur. (C) 2000 Academic Press.