The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin.
The ErbB-1 receptor tyrosine kinase binds to six different growth factors, whose prototype is the epidermal growth factor (EGF). Two homologous epithelial receptors, ErbB-3 and ErbB-4, bind all isoforms of another family of growth factors, the Neu differentiation factors (NDFs/neuregulins). The fourth member of the ErbB family, ErbB-2, acts as the preferred heterodimeric partner of ligand-occupied complexes of the three other ErbB proteins. Here we report that at high concentrations, EGF can induce cell growth and differentiation in the absence of ErbB-1. This function is shared by betacellulin, but not by three other ligands, including the transforming growth factor alpha (TGFalpha). The functional receptor was identified as a heterodimer between ErbB-3 and ErbB-2, a previously identified oncogenic complex. When singly expressed, neither ErbB-3 nor ErbB-2 can mediate signaling by EGF. In addition, when co-expressed, blocking either receptor by using site-specific antibodies inhibited EGF and betacellulin activities, indicating strict cooperativity between ErbB-3 and ErbB-2. Through analysis of chimeras between EGF and TGFalpha, we identified the middle portion of EGF (loop B) as the site that enables activation of ErbB-2/ErbB-3. In conclusion, cooperative and promiscuous binding of stroma-derived growth factors by the epithelium-expressed ErbB-2/ErbB-3 heterodimer may be significant to cancer development. The mechanistic implications of our results for a model that attributes receptor dimerization to ligand bivalency, as well as to a recently proposed mechanism of secondary dimerization, are discussed.
Pinkas-Kramarski
R
R
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
Lenferink
A E
AE
Bacus
S S
SS
Lyass
L
L
van de Poll
M L
ML
Klapper
L N
LN
Tzahar
E
E
Sela
M
M
van Zoelen
E J
EJ
Yarden
Y
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D066259:Betacellulin; D001665:Binding Sites; D001943:Breast Neoplasms; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D020893:Receptor, ErbB-3; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D066259:Betacellulin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011994:Recombinant Proteins; D014443:Tyrosine; C587851:BTC protein, human; C587852:Btc protein, mouse