Coupling of the c-Cbl protooncogene product to ErbB-1/EGF-receptor but not to other ErbB proteins.
The ErbB family of transmembrane tyrosine kinases includes the receptor for EGF (ErbB-1), two receptors for NDF/heregulin (ErbB-3 and ErbB-4) and an orphan receptor (ErbB-2). In order to examine the possibility that distinct signal transduction pathways are coupled to each ErbB protein, we examined the interaction of individual ligand-stimulated receptors with the c-Cbl protein, a protooncogene-encoded signaling molecule previously identified in hematopoietic cells. We report that c-Cbl undergoes rapid and sustained phosphorylation on tyrosine residues upon stimulation of fibroblast and epithelial cell lines with ligands of ErbB-1. By contrast, activation of either ErbB-3 or ErbB-4 by NDF did not affect tyrosine phosphorylation of c-Cbl. Likewise, activation of a chimeric ligand-stimulatable ErbB-2 by a heterologous ligand was ineffective. Despite rapidity of the EGF effect, we observed no association of c-Cbl with activated ErbB-1, implying that the interaction is indirect. Our in vitro experiments suggest that a candidate mediator of the interaction is the Grb-2/Ash adaptor protein, which is constitutively bound to c-Cbl. These results indicate that different ErbB proteins can couple to distinct signaling pathways, and therefore their physiological functions are probably non-redundant.
Levkowitz
G
G
Department of Chemical Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Klapper
L N
LN
Tzahar
E
E
Freywald
A
A
Sela
M
M
Yarden
Y
Y
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D051381:Rats; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases
D008024:Ligands; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C067419:CBL protein, human