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Alternative intracellular routing of ErbB receptors may determine signaling potency
H Waterman1, I Sabanai, B Geiger
1Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Abstract:
The ErbB signaling module consists of four receptor tyrosine kinases and several dozen ligands that activate specific homo- and heterodimeric complexes of ErbB proteins. Combinatorial ligand/receptor/effector interactions allow large potential for signal diversification. Here we addressed the possibility that turn-off mechanisms enhance the diversification potential. Concentrating on ErbB-1 and two of its ligands, epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha), and the Neu differentiation factor (NDF/neuregulin) and one of its receptors, ErbB-3, we show that ligand binding variably accelerates endocytosis of the respective ligand-receptor complex. However, unlike the EGF-activated ErbB-1, which is destined primarily to degradation in lysosomes, NDF and TGF-alpha direct their receptors to recycling, probably because these ligands dissociate from their receptors earlier along the endocytic pathway. In the case of NDF, structural, as well as biochemical, analyses imply that ligand degradation occurs at a relatively late endosomal stage. Attenuation of receptor down-regulation by this mechanism apparently confers to both NDF and TGF-alpha more potent and prolonged signaling activity. In conclusion, alternative endocytic trafficking of ligand-ErbB complexes may tune and diversify signal transduction by EGF family ligands.
Insights
Ligand binding to ErbB receptors affects their endocytosis and trafficking. Different ligands, like epidermal growth factor (EGF) and neuregulin (NDF), influence whether ErbB receptors are degraded or recycled, impacting signal duration.
Area of Science:
- Cellular Biology
- Molecular Signaling
- Receptor Tyrosine Kinases
Background:
- The ErbB signaling network involves four receptor tyrosine kinases and numerous ligands, enabling complex signal diversification through combinatorial interactions.
- Understanding the mechanisms that regulate ErbB signaling, including receptor down-regulation, is crucial for deciphering cellular responses.
Purpose of the Study:
- To investigate whether endocytic trafficking pathways of ligand-ErbB complexes contribute to signal diversification.
- To compare the endocytic fates of ErbB-1 and ErbB-3 receptors upon stimulation with different ligands, specifically epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), and neuregulin (NDF).
Main Methods:
- Comparative analysis of ligand-induced endocytosis and intracellular trafficking of ErbB receptor complexes.
- Biochemical and structural analyses to determine the fate of ligands and receptors within the endocytic pathway.
- Assessment of signaling duration and potency in response to differential receptor trafficking.
Main Results:
- Ligand binding variably accelerates the endocytosis of ErbB receptor complexes.
- Epidermal growth factor (EGF) primarily directs ErbB-1 to lysosomal degradation, while NDF and TGF-alpha promote recycling of their respective receptors.
- Ligand dissociation timing and endosomal degradation stage influence receptor down-regulation, with NDF degradation occurring at a late endosomal stage.
Conclusions:
- Alternative endocytic trafficking pathways for ligand-ErbB complexes diversify signal transduction.
- NDF and TGF-alpha confer more potent and prolonged signaling by attenuating receptor down-regulation through recycling.
- Differential receptor trafficking represents a key mechanism for tuning ErbB-mediated cellular responses.