Abstract

The applicant proposes to test the novel hypothesis that the protein product of the c-cbl protooncogene (Cbl) is a regulator of EGFR/ErbB2 signal transduction in mammary epithelial cells. To test this, the applicant will express the putative EGF-regulatory domain of Cbl (Cbl-N) or its inactive mutant (Cbl-N/G306E) in human MECs and quantify their mitogenic response to EGF, receptor internalization and sub-cellular localization of EGFR/ErbB2. Screening of degenerate phosphopetide libraries, and phosphopeptide competition to identify Cbl-binding site(s) on the EGFR/ErbB2 and mutate these sites to ascertain the nature of Cbl's regulatory influence. The applicant proposes that the accomplishment of this proposal represents a critical step forward to identify new targets for the rational therapeutic strategies against breast cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075075-04
Application #
6173305
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Freeman, Colette S
Project Start
1997-09-19
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
4
Fiscal Year
2000
Total Cost
$250,065
Indirect Cost

  Institution

Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Miura-Shimura, Yuko; Duan, Lei; Rao, Navin L et al. (2003) Cbl-mediated ubiquitinylation and negative regulation of Vav. J Biol Chem 278:38495-504
Singh, Latika; Gao, Qingshen; Kumar, Ajay et al. (2003) The high-risk human papillomavirus type 16 E6 counters the GAP function of E6TP1 toward small Rap G proteins. J Virol 77:1614-20
Zhou, Pengcheng; Fernandes, Norvin; Dodge, Ingrid L et al. (2003) ErbB2 degradation mediated by the co-chaperone protein CHIP. J Biol Chem 278:13829-37
Wang, You jie; Ota, Satoshi; Kataoka, Hideki et al. (2002) Negative regulation of EphA2 receptor by Cbl. Biochem Biophys Res Commun 296:214-20
Zeng, Musheng; Kumar, Ajay; Meng, Gaoyuan et al. (2002) Human papilloma virus 16 E6 oncoprotein inhibits retinoic X receptor-mediated transactivation by targeting human ADA3 coactivator. J Biol Chem 277:45611-8
Kumar, Ajay; Zhao, Yongtong; Meng, Gaoyuan et al. (2002) Human papillomavirus oncoprotein E6 inactivates the transcriptional coactivator human ADA3. Mol Cell Biol 22:5801-12
Rao, Navin; Miyake, Sachiko; Reddi, Alagarsamy Lakku et al. (2002) Negative regulation of Lck by Cbl ubiquitin ligase. Proc Natl Acad Sci U S A 99:3794-9
Gao, Qingshen; Kumar, Ajay; Singh, Latika et al. (2002) Human papillomavirus E6-induced degradation of E6TP1 is mediated by E6AP ubiquitin ligase. Cancer Res 62:3315-21
Rao, Navin; Dodge, Ingrid; Band, Hamid (2002) The Cbl family of ubiquitin ligases: critical negative regulators of tyrosine kinase signaling in the immune system. J Leukoc Biol 71:753-63
Peschard, P; Fournier, T M; Lamorte, L et al. (2001) Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. Mol Cell 8:995-1004

Showing the most recent 10 out of 18 publications