ErbB4 signals Neuregulin1-stimulated cell proliferation and c-fos gene expression through phosphorylation of serum response factor by mitogen-activated protein kinase cascade.

The ErbB family of tyrosine kinase receptors mediates a variety of cellular responses to Neuregulin (NRG) 1; however, the intracellular signaling pathways downstream of ErbB4 and their functional outcomes remained to be elucidated. Here we show that NRG1 stimulated the proliferation of human HeLa cells expressing ErbB4, where the phosphorylation relay of extracellular signal-regulated kinase, a mitogen-activated protein kinase (MAPK), and serum response factor (SRF), a transcription factor, was induced, and the c-fos transcription was activated. By contrast, these all were attenuated in cells transfected with an ErbB4 mutant substituting the green fluorescence protein for the intracellular domain. We also demonstrated that a MAPK kinase inhibitor suppressed the NRG1-stimulated SRF phosphorylation, c-fos expression, and cell proliferation. Thus, the current study may unravel an ErbB4-mediated signaling pathway that is responsible for the NRG1-induced c-fos gene expression through the MAPK cascade-dependent SRF phosphorylation and thereby cell proliferation.