The Target Sites on EGF Receptor for Cbl, It's Negative Regulator
Abstract
Activation of tyrosine kinases plays a key role in breast cancer cell proliferation. ErbB receptors and Src-family tyrosine kinases are specifically implicated in breast cancer. Earlier, we showed that Cbl, a negative regulator of EGF receptor (ErbBl), enhances sorting of the activated EGFR into lysosomes as opposed to its recycling to the cell surface. These findings, together with studies implicating Src-family kinases as positive modulators of EGFR signaling, led to a shift in our focus to examine the potential negative regulatory role of Cbl for Src-family kinases. Work reported here provides multiple lines of evidence that Cbl indeed functions as a negative regulator of Fyn, a prototype Src-family kinase, and that this effect is exerted through enhancement of Fyn degradation. These results support the role of protein degradation as a general mechanism for cbl-mediated negative regulation of activated tyrosine kinases and provide a second mechanism for its role in attenuating ErbB signals. Future work will explore the mechanisms of Cbl-induced degradation of Src-family kinases and identify the signaling compartments where ErbB receptors are targeted as a result of their interaction with Src- family kinases. The proposed studies are aimed at defining novel strategies to downregulate proliferative signals in breast cancer cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2000
- Accession Number
- ADA384088
Entities
People
- Christopher E. Andoniou
- Hamid Band
Organizations
- Brigham and Women's Hospital