ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer.
Overexpression of the erbB-2 gene contributes to aggressive behavior of various human adenocarcinomas, including breast cancer, through an unknown molecular mechanism. The erbB-2-encoded protein is a member of the ErbB family of growth factor receptors, but no direct ligand of ErbB-2 has been reported. We show that in various cells ErbB-2 can form heterodimers with both EGF receptor (ErbB-1) and NDF receptors (ErbB-3 and ErbB-4), suggesting that it may affect the action of heterologous ligands without the involvement of a direct ErbB-2 ligand. This possibility was addressed in breast cancer cells through either overexpression of ErbB-2 or by blocking its delivery to the cell surface by means of an endoplasmic reticulum-trapped antibody. We report that ErbB-2 overexpression enhanced binding affinities to both EGF and NDF, through deceleration of ligand dissociation rates. Likewise, removal of ErbB-2 from the cell surface almost completely abolished ligand binding by accelerating dissociation of both growth factors. The kinetic effects resulted in enhancement and prolongation of the stimulation of two major cytoplasmic signaling pathways, namely: MAP kinase (ERK) and c-Jun kinase (SAPK), by either ligand. Our results imply that ErbB-2 is a pan-ErbB subunit of the high affinity heterodimeric receptors for NDF and EGF. Therefore, the oncogenic action of ErbB-2 in human cancers may be due to its ability to potentiate in trans growth factor signaling.
Karunagaran
D
D
Departement of Chemical Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Tzahar
E
E
Beerli
R R
RR
Chen
X
X
Graus-Porta
D
D
Ratzkin
B J
BJ
Seger
R
R
Hynes
N E
NE
Yarden
Y
Y
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016466:CHO Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000096:biosynthesis / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D018734:Genes, erbB-2; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D046911:Macromolecular Substances; D020880:Neuregulins; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D006023:Glycoproteins; D046911:Macromolecular Substances; D020880:Neuregulins; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D011994:Recombinant Proteins; C587689:ERBB4 protein, human