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c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor
G Levkowitz1, H Waterman, E Zamir
1Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Abstract:
Ligand-induced down-regulation of two growth factor receptors, EGF receptor (ErbB-1) and ErbB-3, correlates with differential ability to recruit c-Cbl, whose invertebrate orthologs are negative regulators of ErbB. We report that ligand-induced degradation of internalized ErbB-1, but not ErbB-3, is mediated by transient mobilization of a minor fraction of c-Cbl into ErbB-1-containing endosomes. This recruitment depends on the receptor's tyrosine kinase activity and an intact carboxy-terminal region. The alternative fate is recycling of internalized ErbBs to the cell surface. Cbl-mediated receptor sorting involves covalent attachment of ubiquitin molecules, and subsequent lysosomal and proteasomal degradation. The oncogenic viral form of Cbl inhibits down-regulation by shunting endocytosed receptors to the recycling pathway. These results reveal an endosomal sorting machinery capable of controlling the fate, and, hence, signaling potency, of growth factor receptors.
Insights
Ligand binding triggers growth factor receptor down-regulation via c-Cbl. This study reveals how c-Cbl sorts internalized EGF receptors (ErbB-1) for degradation, controlling cell signaling.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- Growth factor receptors like EGF receptor (ErbB-1) and ErbB-3 play crucial roles in cell growth and are regulated by ligand-induced down-regulation.
- The protein c-Cbl acts as a negative regulator of ErbB signaling, influencing receptor fate after internalization.
Purpose of the Study:
- To investigate the mechanism by which c-Cbl mediates the ligand-induced degradation of internalized ErbB-1 and ErbB-3.
- To elucidate the role of receptor tyrosine kinase activity and the carboxy-terminal region in c-Cbl recruitment.
Main Methods:
- Studied ligand-induced receptor internalization and endosomal trafficking.
- Investigated the recruitment of c-Cbl to endosomes containing ErbB-1 and ErbB-3.
- Analyzed the role of tyrosine kinase activity and receptor structure in c-Cbl-mediated sorting.
- Examined the impact of ubiquitin conjugation and the viral form of Cbl on receptor fate.
Main Results:
- Ligand-induced degradation of internalized ErbB-1, but not ErbB-3, is dependent on transient c-Cbl mobilization into ErbB-1 endosomes.
- c-Cbl recruitment requires the receptor's tyrosine kinase activity and an intact carboxy-terminal region.
- Cbl-mediated sorting involves ubiquitination, leading to lysosomal and proteasomal degradation, while the viral Cbl form promotes receptor recycling.
Conclusions:
- An endosomal sorting machinery controlled by c-Cbl dictates the fate of internalized growth factor receptors.
- This machinery regulates receptor signaling potency by directing receptors towards degradation or recycling pathways.
- Understanding this pathway is crucial for comprehending cell signaling control and potential therapeutic interventions.