The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors.
The erbB-2/HER2 oncogene is overexpressed in a significant fraction of human carcinomas of the breast, ovary, and lung in a manner that correlates with poor prognosis. Although the encoded protein resembles several receptors for growth factors, no high affinity ligand of ErbB-2 has so far been fully characterized. However, several lines of evidence have raised the possibility that ErbB-2 can augment signal transduction initiated by binding of certain growth factors to their direct receptors. Here, we contrasted these two models of ErbB-2 function: First, examination of a large series of epidermal growth factor (EGF)-like ligands and neuregulins, including virus-encoded ligands as well as related motifs derived from the precursor of EGF, failed to detect interactions with ErbB-2 when this protein was singly expressed. Second, by using antibodies that block inter-ErbB interactions and cells devoid of surface ErbB-2, we learned that signaling by all ligands examined, except those derived from the precursor of EGF, was enhanced by the oncoprotein. These results imply that ErbB-2 evolved as a shared receptor subunit of all ErbB-specific growth factors. Thus, oncogenicity of ErbB-2 in human epithelia may not rely on the existence of a specific ligand but rather on its ability to act as a coreceptor for multiple stroma-derived growth factors.
Klapper
L N
LN
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Glathe
S
S
Vaisman
N
N
Hynes
N E
NE
Andrews
G C
GC
Sela
M
M
Yarden
Y
Y
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D018734:Genes, erbB-2; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009414:Nerve Growth Factors / Q000378:metabolism; D020880:Neuregulins; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells; D014407:Tumor Cells, Cultured
D004815:Epidermal Growth Factor; D006023:Glycoproteins; D008024:Ligands; D009414:Nerve Growth Factors; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases; D018160:Receptors, Cytoplasmic and Nuclear