Abstract
Signaling by the epidermal growth factor (EGF) family and the neuregulin group of ligands is mediated by four ErbB receptor tyrosine kinases, that form homo- and heterodimeric complexes. Paradoxically, the neuregulin receptor ErbB-3 is devoid of catalytic activity, but its heterodimerization with other ErbBs, particularly the ligand-less ErbB-2 oncoprotein of carcinomas, reconstitutes superior mitogenic and transforming activities. To understand the underlying mechanism we constructed a chimeric EGF-receptor (ErbB-1) whose autophosphorylation C-terminal domain was replaced by the corresponding portion of ErbB-3. Consistent with the possibility that this domain recruits a relatively potent signaling pathway(s), the mitogenic signals generated by the recombinant fusion protein were superior to those generated by ErbB-1 homodimers and comparable to the proliferative activity of ErbB-2/ErbB-3 heterodimers. Upon ligand binding, the chimeric receptor recruited an ErbB-3-specific repertoire of signaling proteins, including Shc and the phosphatidylinositol 3-kinase, but excluding the ErbB-1-specific substrate, phospholipase Cgamma1. Unlike ErbB-1, which is destined to lysosomal degradation through a mechanism that includes recruitment of c-Cbl and receptor poly-ubiquitination, the C-terminal tail of ErbB-3 shunted the chimeric protein to the ErbB-3-characteristic recycling pathway. These observations attribute the mitogenic superiority of ErbB-3 to its C-terminal tail and imply that the flanking kinase domain has lost catalytic activity in order to restrain the relatively potent signaling capability of the C-terminus.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adaptor Proteins, Vesicular Transport*
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Animals
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Cell Division / drug effects
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Cell Line
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Cell Survival / drug effects
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Dimerization
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Down-Regulation / drug effects
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Endocytosis* / drug effects
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / chemistry*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Glycoproteins / pharmacology
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Humans
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Isoenzymes / metabolism
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Mitogens / pharmacology*
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Neuregulins
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Phosphatidylinositol 3-Kinases / metabolism
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Phospholipase C gamma
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Phosphorylation / drug effects
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Protein Kinases / chemistry
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Proteins / metabolism
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Proto-Oncogene Proteins / chemistry*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-cbl
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Receptor, ErbB-3
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Shc Signaling Adaptor Proteins
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Signal Transduction / drug effects
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Type C Phospholipases / metabolism
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Ubiquitin-Protein Ligases*
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Glycoproteins
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Isoenzymes
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Mitogens
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Neuregulins
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Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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SHC1 protein, human
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Shc Signaling Adaptor Proteins
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Epidermal Growth Factor
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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Protein Kinases
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Phosphatidylinositol 3-Kinases
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ErbB Receptors
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Receptor, ErbB-3
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Type C Phospholipases
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Phospholipase C gamma
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CBL protein, human