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Src promotes destruction of c-Cbl: implications for oncogenic synergy between Src and growth factor receptors
Jing Bao1, Gal Gur, Yosef Yarden
1Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Abstract:
Cellular Src and epidermal growth factor receptor (EGFR) collaborate in the progression of certain human malignancies, and their cooverexpression characterizes relatively aggressive animal tumors. Our study addressed the mode of oncogenic cooperation and reports that overexpression of c-Src in model cellular systems results in the accumulation of EGFR at the cell surface. The underlying mechanism involves inhibition of the normal, c-Cbl-regulated process of ligand-induced receptor down-regulation. In response to activation of c-Src, c-Cbl proteins undergo tyrosine phosphorylation that promotes their ubiquitylation and proteasomal destruction. Consequently, ubiquitylation of EGFR by c-Cbl is restrained in Src-transformed cells, and receptor sorting to endocytosis is impaired. In conclusion, by promoting destruction of c-Cbl, c-Src enables EGFR to evade desensitization, which explains Src-EGFR collaboration in oncogenesis.
Insights
Overexpression of c-Src kinase in cancer leads to epidermal growth factor receptor (EGFR) accumulation by preventing its degradation. This Src-EGFR collaboration drives oncogenesis by inhibiting normal receptor down-regulation.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Signaling
Background:
- Cellular Src (c-Src) and epidermal growth factor receptor (EGFR) are key players in human cancer progression.
- Co-overexpression of c-Src and EGFR is linked to aggressive tumors in animal models.
Purpose of the Study:
- To elucidate the mechanism of oncogenic cooperation between c-Src and EGFR.
- To understand how c-Src overexpression impacts EGFR regulation and cell surface levels.
Main Methods:
- Utilized model cellular systems to study c-Src overexpression effects.
- Investigated the role of c-Cbl in regulating EGFR down-regulation.
- Analyzed tyrosine phosphorylation, ubiquitylation, and proteasomal degradation pathways.
Main Results:
- c-Src overexpression causes EGFR accumulation on the cell surface.
- c-Src activation leads to tyrosine phosphorylation and proteasomal destruction of c-Cbl.
- Inhibition of c-Src-mediated c-Cbl destruction impairs EGFR ubiquitylation and endocytosis.
Conclusions:
- c-Src promotes EGFR accumulation by disrupting c-Cbl-mediated degradation.
- This mechanism explains the collaborative oncogenic role of Src and EGFR in malignancies.
- Targeting c-Src-c-Cbl-EGFR interactions may offer therapeutic strategies for aggressive cancers.