v-Cbl is the transforming gene of the Cas NS-1 retrovirus that induces hematopoietic malignancies in mice. c-Cbl, the cellular homolog of v- Cbl, is inducibly tyrosine phosphorylated in normal cells in response to a variety of proliferation and activation signals. Mutations of c-Cbl that activate its transforming potential induce tyrosine phosphorylation of Cbl and c-Cbl is tyrosine phosphorylated in cells transformed by activated Abl tyrosine kinases. In Abl-transformed cells, tyrosine phosphorylated Cbl associates with the SH2 domains of activated Abl, CrkL, and PI 3-kinase. Further, the spectrum of tumors induced in mice by v-Abl are phenotypically and histologically similar to those induced by v-Cbl. It is the investigators hypothesis that tyrosine phosphorylation of Cbl has an important role in regulating the function of Cbl and that Cbl may have a critical role in mediating transformation by activated Abl.
The specific aims of this project are to determine whether Cbl can transform myeloid cells to growth factor independence; to analyze the role of Cbl tyrosine phosphorylation by identifying tyrosine residues of Cbl that are phosphorylated by the Abl and epidermal growth factor receptor (EGFR) tyrosine kinases and to analyze these sites for interactions with SH2 domain-containing proteins, and determining whether mutations of tyrosine phosphorylation sites affect Cbl function. Lastly, the role of Cbl in transformation by Bcr-Abl will be investigated. Through these studies the investigators should gain a greater understanding of the contribution of tyrosine phosphorylation of Cbl to its function and the role of Cbl in myeloid transformation.
