ErbB‐4 Activation Promotes Neurite Outgrowth in PC12 Cells

Abstract

Abstract: Neu differentiation factor (NDF; also known as neuregulin) induces a pleiotropic cellular response that is cell type‐dependent. NDF and its receptor ErbB‐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 that are indistinguishable from those mediated by the nerve growth factor‐activated Trk receptors. In PC12‐ErbB‐4 cells but not in PC12 cells, NDF induced an initial weak mitogenic signal and subsequently neurite outgrowth. The NDF‐induced differentiation in PC12‐ErbB‐4 cells was mimicked by the pan‐ErbB ligand betacellulin but not by other epidermal growth factor‐like ligands. Thus, NDF and betacellulin mediate similar activities through the ErbB‐4 receptor. Indeed, only these ligands induced strong phosphorylation of the 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. Inhibition of the MAPK kinase MEK or of protein kinase C (PKC) blocked NDF‐induced differentiation, whereas elevation of cyclic AMP levels enhanced the response. Taken together, these results indicate that neurite outgrowth induced by ErbB‐4 in PC12 cells requires MAPK and PKC signaling networks.

Keywords

Affiliated Institutions

• Tel Aviv University IL

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