Neuregulin 1-activated ERBB4 interacts with YAP to induce Hippo pathway target genes and promote cell migration

Sci Signal. 2014 Dec 9;7(355):ra116. doi: 10.1126/scisignal.2005770.

Abstract

The receptor tyrosine kinase ERBB4, a member of the epidermal growth factor receptor (EGFR) family, is unusual in that ERBB4 can undergo intramembrane proteolysis, releasing a soluble intracellular domain (ICD) that modulates transcription in the nucleus. We found that ERBB4 activated the transcriptional coactivator YAP, which promotes organ and tissue growth and is inhibited by the Hippo tumor-suppressor pathway. Overexpressing ERBB4 in cultured mammary epithelial cells or adding the ERBB4 ligand neuregulin 1 (NRG1) to breast cancer cell cultures promoted the expression of genes regulated by YAP, such as CTGF. Knocking down YAP or ERBB4 prevented the induction of CTGF expression by NRG1, as did treating cells with the ERBB inhibitors lapatinib or erlotinib, which reduced ERBB4 cleavage. NRG1 stimulated YAP activity to an extent comparable to that of EGF (epidermal growth factor) or LPA (lysophosphatidic acid), known activators of YAP. NRG1 stimulated YAP-dependent cell migration in breast cancer cell lines. These observations connect the unusual nuclear function of a growth factor receptor with a mechanosensory pathway and suggest that NRG1-ERBB4-YAP signaling contributes to the aggressive behavior of tumor cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Movement*
  • Connective Tissue Growth Factor / biosynthesis
  • Connective Tissue Growth Factor / genetics
  • Erlotinib Hydrochloride
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Knockdown Techniques
  • Hippo Signaling Pathway
  • Humans
  • Lapatinib
  • Mechanotransduction, Cellular*
  • Neuregulin-1 / genetics
  • Neuregulin-1 / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Quinazolines / pharmacology
  • Receptor, ErbB-4 / antagonists & inhibitors
  • Receptor, ErbB-4 / genetics
  • Receptor, ErbB-4 / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • CCN2 protein, human
  • Cell Cycle Proteins
  • NRG1 protein, human
  • Neuregulin-1
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Quinazolines
  • Transcription Factors
  • YY1AP1 protein, human
  • Lapatinib
  • Connective Tissue Growth Factor
  • Erlotinib Hydrochloride
  • ERBB4 protein, human
  • Receptor, ErbB-4
  • Protein Serine-Threonine Kinases