Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family

Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1746-50. doi: 10.1073/pnas.90.5.1746.


This report describes the isolation and recombinant expression of a cDNA clone encoding HER4, the fourth member of the human epidermal growth factor receptor (EGFR) family. The HER4/erbB4 gene encodes a 180-kDa transmembrane tyrosine kinase (HER4/p180erbB4) whose extracellular domain is most similar to the orphan receptor HER3/p160erbB3, whereas its cytoplasmic kinase domain exhibits 79% and 77% identity with EGFR and HER2/p185erbB2, respectively. HER4 is most predominantly expressed in several breast carcinoma cell lines, and in normal skeletal muscle, heart, pituitary, brain, and cerebellum. In addition, we describe the partial purification of a heparin-binding HER4-stimulatory factor from HepG2 cells. This protein was found to specifically stimulate the intrinsic tyrosine kinase activity of HER4/p180erbB4 while having no direct effect on the phosphorylation of EGFR, HER2, or HER3. Furthermore, this heparin-binding protein induces phenotypic differentiation, and tyrosine phosphorylation, of a human mammary tumor cell line that overexpresses both HER4 and HER2. These findings suggest that this ligand-receptor interaction may play a role in the growth and differentiation of some normal and transformed cells.

Publication types

  • Comparative Study

MeSH terms

  • Base Sequence
  • Cells
  • Cloning, Molecular
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • ErbB Receptors / physiology*
  • Gene Expression
  • Ligands
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Molecular Sequence Data
  • Oligodeoxyribonucleotides / chemistry
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism
  • RNA, Messenger / genetics
  • Receptor, ErbB-4
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / physiology
  • Sequence Alignment
  • Signal Transduction
  • Tissue Distribution


  • Ligands
  • Membrane Glycoproteins
  • Oligodeoxyribonucleotides
  • RNA, Messenger
  • Receptors, Cell Surface
  • ERBB4 protein, human
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-4

Associated data

  • GENBANK/L07868