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Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor
R Pinkas-Kramarski1, L Soussan, H Waterman
1Department of Molecular Cell Biology, Weizmann Institute of Science, Israel.
Abstract:
The ErbB family includes two receptors, ErbB-1 and ErbB-3, that respectively bind to epidermal growth factor and Neu differentiation factor, and an orphan receptor, ErbB-2. Unlike ErbB-1 and ErbB-2, the intrinsic tyrosine kinase of ErbB-3 is catalytically impaired. By using interleukin-3-dependent cells that ectopically express the three ErbB proteins or their combinations, we found that ErbB-3 is devoid of any biological activity but both ErbB-1 and ErbB-2 can reconstitute its extremely potent mitogenic activity. Transactivation of ErbB-3 correlates with heterodimer formation and is reflected in receptor phosphorylation and the transregulation of ligand affinity. Inter-receptor interactions enable graded proliferative and survival signals: heterodimers are more potent than homodimers, and ErbB-3-containing complexes, especially the ErbB-2/ErbB-3 heterodimer, are more active than ErbB-1 complexes. Nevertheless, ErbB-1 signaling displays dominance over ErbB-3 when the two receptors are coexpressed. Although all receptor combinations activate the mitogen-activated protein kinases ERK and c-Jun kinase, they differ in their rate of endocytosis and in coupling to intervening signaling proteins. It is conceivable that combinatorial receptor interactions diversify signal transduction and confer double regulation, in cis and in trans, of the superior mitogenic activity of the kinase-defective ErbB-3.
Insights
Epidermal Growth Factor Receptor (EGFR) family members ErbB-1 and ErbB-2 restore potent mitogenic activity to the kinase-impaired ErbB-3 receptor. Combinatorial ErbB interactions diversify signaling, with ErbB-3 complexes showing enhanced activity.
Area of Science:
- Cellular Biology
- Molecular Biology
- Signal Transduction
Background:
- The ErbB receptor family plays crucial roles in cell growth and survival.
- ErbB-1 and ErbB-2 are active tyrosine kinases, while ErbB-3 possesses a catalytically impaired kinase domain.
- ErbB-2 is an orphan receptor, meaning its natural ligand is unknown.
Purpose of the Study:
- To investigate the biological activity of ErbB-3 and its reconstitution by other ErbB family members.
- To elucidate the mechanisms of transactivation and signal diversification within ErbB receptor complexes.
- To analyze the impact of heterodimerization on mitogenic signaling potency.
Main Methods:
- Utilized interleukin-3-dependent cells engineered to express ErbB-1, ErbB-2, and ErbB-3.
- Assessed receptor activity through ectopic expression of individual receptors and their combinations.
- Analyzed receptor phosphorylation, heterodimer formation, and activation of downstream kinases (ERK, c-Jun).
Main Results:
- ErbB-3 alone exhibits no biological activity; ErbB-1 and ErbB-2 reconstitute its potent mitogenic activity.
- Transactivation of ErbB-3 involves heterodimer formation, receptor phosphorylation, and ligand affinity regulation.
- ErbB-3-containing heterodimers, particularly ErbB-2/ErbB-3, demonstrate superior mitogenic and survival signaling compared to homodimers.
- ErbB-1 signaling dominates over ErbB-3 when coexpressed, despite ErbB-3's enhanced activity in complexes.
Conclusions:
- Combinatorial interactions among ErbB receptors diversify signal transduction pathways.
- Heterodimerization, especially involving ErbB-3, significantly enhances mitogenic and survival signaling.
- The kinase-defective ErbB-3 receptor's superior activity is regulated in cis and in trans through complex formation.