STAUROSPORINE CAUSES EPIDERMAL GROWTH-FACTOR TO INDUCE DIFFERENTIATION IN PC12 CELLS VIA RECEPTOR UP-REGULATION

Although they all utilize tyrosine kinase receptors and activate signa ling pathways characterized by a similar set of phosphoproteins, epide rmal growth factor (EGF) promotes only cell division while fibroblast growth factor (FGF) and nerve growth factor (NGF) can induce division followed by differentiation in PC12 cells, EGF, in contrast to NGF and FGF, cannot maintain the sustained phosphorylation and activation of mitogen-activated protein (MAP) kinase kinase and MAP kinases, which m ay account for the difference in phenotypic response. The pretreatment of PC12 cells with staurosporine, a protein kinase inhibitor, causes a substantial increase in both receptor and MAP kinase phosphorylation that results in a differentiative response (neurite proliferation). H owever, neurites begin to dis appear after 3 days, despite the continu al presence of EGP, and are largely gone after 5 days, which is not th e case with NGF and FGF. Thus, the effect of staurosporine is not perm anent. Northern and Western blots indicate that the staurosporine resp onse mainly results from a substantial up-regulation in EGF receptor s ynthesis, thus providing a much stronger cell surface signal and suppo rting the view that quantitative rather than qualitative differences d istinguish the EGF versus NGF/FGF signaling pathways in these cells.