Due to their overexpression in the presence or absence of gene amplification, the erbB family of receptor tyrosine kinases have frequently been implicated in neoplasia, especially in breast cancer. We have recently demonstrated that erbB-3 and erbB-2 cooperate in neoplastic transformation of NIH 3T3. Cooperation involved heterodimer formation and increase in P13 kinases activity. Our evidence for signaling by an active erbB-3 and erbB-2 heterodimer in four mammary tumor cell lines indicates relevance of this mechanism for human neoplasia. The goal of this proposal is to dissect the mechanism for cooperation between erbB-2 and erbB-3 at the molecular level. We propose to analyze the structural requirements of heterodimer receptor interaction by mapping specific domains in the erbB-3 sequence using different structurally-altered erbB-3 proteins generated by site-directed mutagenesis.
In Aims 1 and 2 respectively, we will analyze the role of the catalytic domain and the extracellular domain in mediating the cooperative transformation with erbB-2 and the mechanisms of activation of the unusual erbB-3 tyrosine kinase. The carboxyl-terminal domains of growth factor receptors have the specific function of modulating the binding with the signaling molecule.
In Aim 3, we will use a truncated erbB-3 receptor to study both the role of this region in the cooperation with erbB-2 and the importance of the Pl3 kinase signaling pathway in NIH 3T3 transformation. Understanding the cooperation between these two receptors will be importance for evaluating the prognostic value of the expression of the erbB-2 and erbB-3 oncogenes in human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA071997-03
Application #
2895686
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Freeman, Colette S
Project Start
1997-04-15
Project End
2002-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029