The long-term goal of this research is to elucidate the biological role of the cAbl proto-oncogene. The cAbl protein is a tyrosine kinase of unknown function. Biochemical data suggest that cAbl may regulate signal transduction events in the cytoplasm and processes in the nucleus. cAbl localizes to both the cytoplasm and the nucleus and contains multiple modular domains. The N-terminal sequences of the protein contain protein interaction domains (SH2 and SH3), while the C-terminal sequences contain a DNA-binding and an actin-binding domain. The tyrosine kinase and transforming activities of cAbl are tightly regulated in vivo. Oncogenic activation of cAbl has been shown to occur as a consequence of structural alterations in the N- or C-terminal sequences of the protein. Altered forms of cAbl are associated with the induction of murine, feline and human leukemias. Elucidation of a biological role for the cAbl tyrosine kinase has been hampered for over a decade by lack of knowledge regarding its mechanism of activation and the lack of biologically relevant, specific in vivo substrates for its tyrosine kinase activity.
The specific aims of this proposal are: 1) to identify and characterize direct upstream regulators and downstream effectors of cAbl by a combination of molecular biological, biochemical and genetic techniques; and 2) to define the cellular signals that lead to activation of the cAbl tyrosine kinase. They have succeeded in identifying a protein that interacts directly with cAbl in vitro and in vivo. Like cAbl, the Abl-interacting protein 1 (Aip1) localizes to the cytoplasm and the nucleus. Aip1 contains two domains that interact with at least two surfaces on the cAbl molecule. Significantly, Aipl also contains a unique potential DNA-binding domain that exhibits homology to homeodomains. Recently, they have uncovered a mechanism for activating the cAbl tyrosine kinase in intact cells. Activation of cAbl leads to tyrosine phosphorylation of the associated Aipl in vivo. Aip-1 is also an excellent substrate of the cAbl tyrosine kinase in vitro. Aip1 belongs to a family of proteins that may function to transduce signals from the cytoplasmic SH3/SH2-containing protein tyrosine kinases to specific compartments within the cytoplasm or directly into the nucleus. Analysis of the biochemical and biological roles of Aipl and related family members will be carried out. The role of Aips, following activation of the cAbl tyrosine kinase in normal and transformed cells will be analyzed. Deregulation of cAbl function as a consequence of alterations of the associated Aips may lead to the induction of a number of human cancers.
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