An unusual mechanism of ERBB4 in regulating tumor related gene expression


ERBB4 is a receptor tyrosine kinase of the epidermal growth factor receptor (EGFR/ERBB) family. Unlike other EGFR family members, ERBB4 regulates target gene expression via releasing a soluble intracellular domain (ICD). Haskins et al. found ERBB4 activated the transcriptional coactivator YAP by binding to its ligand neuregulin 1 (NRG1), to regulate gene expression of cancer cells. The article was published on Sciense Signaling, recently.


By undergoing intramembrane proteolysis, ERBB4 releases ICD to the nucleus and cooperates with its coactivator, such as YAP, which is a growth factor of tumor development and progression that can be inhibited by the tumor-suppressor Hippo pathway. NRG1 actives YAP with a similar extent compared with two well known YAP activator, epidermal growth factor (EGF) and lysophosphatidic acid (LPA). The activated YAP increases expression level of target genes, such as CTGF, in cultured mammary epithelial cells or breast cancer cells. In the other way, either knocking down YAP/ERBB4 or inhibiting ERBB4 by lapatinib or erlotinib suppresses the expression of CTGF in the presence of NRG1. The study reveals an unusual mechanism of ERBB4 in gene regulation, and demonstrates the important role of NRG1-ERBB4-YAP signaling pathway in promoting tumor development and progression.


Sci Signal. 2014 Dec 9;7(355):ra116.

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