ErbB-4 activation promotes neurite outgrowth in PC12 cells.
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.
Vaskovsky
A
A
Department of Neurobiochemistry, Tel-Aviv University, Ramat-Aviv, Israel.
Lupowitz
Z
Z
Erlich
S
S
Pinkas-Kramarski
R
R
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology*; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D020932:Nerve Growth Factor / Q000494:pharmacology; D020890:Neuregulin-1 / Q000494:pharmacology; D016501:Neurites / Q000502:physiology*; D016716:PC12 Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D066247:Receptor, ErbB-4; D014443:Tyrosine / Q000378:metabolism
D008024:Ligands; D020890:Neuregulin-1; D014443:Tyrosine; D004815:Epidermal Growth Factor; D020932:Nerve Growth Factor; D000242:Cyclic AMP; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases