ErbB-4 activation promotes neurite outgrowth in PC12 cells

Neu differentiation factor (NDF; also known as neuregulin) induces a pleiot ropic cellular response that is cell type-dependent. NDF and its receptor E rbB-4 are highly expressed in neurons, implying important roles in neuronal cell functions, In the present study we demonstrate that ErbB-4 receptors expressed in PC12 cells mediate NDF-induced signals and neurite outgrowth t hat are indistinguishable from those mediated by the nerve growth factor-ac tivated Trk receptors. In PC12-ErbB-4 cells but not in PC12 cells, NDF indu ced an initial weak mitogenic signal and subsequently neurite outgrowth. Th e NDF-induced differentiation in PC12-ErbB-4 cells was mimicked by the pan- ErbB ligand betacellulin but not by other epidermal growth factor-like liga nds. Thus, NDF and betacellulin mediate similar activities through the ErbB -4 receptor. Indeed, only these ligands induced strong phosphorylation of t he ErbB-4 receptors, Neurite outgrowth induced by NDF in PC12-ErbB-4 cells was accompanied by sustained activation of mitogen-activated protein kinase (MAPK) and induction of the neural differentiation marker GAP-43, Inhibiti on of the MAPK kinase MEK or of protein kinase C (PKC) blocked NDF-induced differentiation, whereas elevation of cyclic AMP levels enhanced the respon se. Taken together, these results indicate that neurite outgrowth induced b y ErbB-4 in PC12 cells requires MAPK and PKC signaling networks.