Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family.
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.
Plowman
G D
GD
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
Culouscou
J M
JM
Whitney
G S
GS
Green
J M
JM
Carlton
G W
GW
Foy
L
L
Neubauer
M G
MG
Shoyab
M
M
D001483:Base Sequence; D002477:Cells; D003001:Cloning, Molecular; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D066247:Receptor, ErbB-4; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology; D016415:Sequence Alignment; D015398:Signal Transduction; D014018:Tissue Distribution
D008024:Ligands; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D066247:Receptor, ErbB-4