ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling.
We have analyzed ErbB receptor interplay induced by the epidermal growth factor (EGF)-related peptides in cell lines naturally expressing the four ErbB receptors. Down-regulation of cell surface ErbB-1 or ErbB-2 by intracellular expression of specific antibodies has allowed us to delineate the role of these receptors during signaling elicited by: EGF and heparin binding EGF (HB-EGF), ligands of ErbB-1; betacellulin (BTC), a ligand of ErbB-1 and ErbB-4; and neu differentiation factor (NDF), a ligand of ErbB-3 and ErbB-4. Ligand-induced ErbB receptor heterodimerization follows a strict hierarchy and ErbB-2 is the preferred heterodimerization partner of all ErbB proteins. NDF-activated ErbB-3 or ErbB-4 heterodimerize with ErbB-1 only when no ErbB-2 is available. If all ErbB receptors are present, NDF receptors preferentially dimerize with ErbB-2. Furthermore, EGF- and BTC-induced activation of ErbB-3 is impaired in the absence of ErbB-2, suggesting that ErbB-2 has a role in the lateral transmission of signals between other ErbB receptors. Finally, ErbB-1 activated by all EGF-related peptides (EGF, HB-EGF, BTC and NDF) couples to SHC, whereas only ErbB-1 activated by its own ligands associates with and phosphorylates Cbl. These results provide the first biochemical evidence that a given ErbB receptor has distinct signaling properties depending on its dimerization.
Graus-Porta
D
D
Friedrich Miescher Institute, Basel, Switzerland.
Beerli
R R
RR
Daly
J M
JM
Hynes
N E
NE
D066259:Betacellulin; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000302:isolation & purification / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D008954:Models, Biological; D008961:Models, Structural; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D014846:Vulvar Neoplasms
D066259:Betacellulin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D006023:Glycoproteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D020880:Neuregulins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; C587851:BTC protein, human