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.
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Authors | H Waterman, I Alroy, S Strano, R Seger, Y Yarden |
Journal | The EMBO journal
(EMBO J)
Vol. 18
Issue 12
Pg. 3348-58
(Jun 15 1999)
ISSN: 0261-4189 [Print] England |
PMID | 10369675
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Adaptor Proteins, Signal Transducing
- Adaptor Proteins, Vesicular Transport
- Glycoproteins
- Isoenzymes
- Mitogens
- Neuregulins
- Proteins
- Proto-Oncogene Proteins
- Recombinant Fusion Proteins
- SHC1 protein, human
- Shc Signaling Adaptor Proteins
- Src Homology 2 Domain-Containing, Transforming Protein 1
- Epidermal Growth Factor
- Proto-Oncogene Proteins c-cbl
- Ubiquitin-Protein Ligases
- Protein Kinases
- Phosphatidylinositol 3-Kinases
- ErbB Receptors
- Receptor, ErbB-3
- Type C Phospholipases
- Phospholipase C gamma
- CBL protein, human
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Topics |
- Adaptor Proteins, Signal Transducing
- Adaptor Proteins, Vesicular Transport
- Animals
- Cell Division
(drug effects)
- Cell Line
- Cell Survival
(drug effects)
- Dimerization
- Down-Regulation
(drug effects)
- Endocytosis
(drug effects)
- Epidermal Growth Factor
(pharmacology)
- ErbB Receptors
(chemistry, genetics, metabolism)
- Glycoproteins
(pharmacology)
- Humans
- Isoenzymes
(metabolism)
- Mitogens
(pharmacology)
- Neuregulins
- Phosphatidylinositol 3-Kinases
(metabolism)
- Phospholipase C gamma
- Phosphorylation
(drug effects)
- Protein Kinases
(chemistry, genetics, metabolism)
- Proteins
(metabolism)
- Proto-Oncogene Proteins
(chemistry, genetics, metabolism)
- Proto-Oncogene Proteins c-cbl
- Receptor, ErbB-3
- Recombinant Fusion Proteins
(biosynthesis, chemistry, genetics, metabolism)
- Shc Signaling Adaptor Proteins
- Signal Transduction
(drug effects)
- Src Homology 2 Domain-Containing, Transforming Protein 1
- Type C Phospholipases
(metabolism)
- Ubiquitin-Protein Ligases
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