The long term objective of this research is to elucidate the biological role of the c-Able proto-oncogene. Mutant forms of c-Abl are associated with the development of murine, feline and human leukemias. Elucidation of a biological role for the c-Abl tyrosine kinase has been hampered for nearly 20 years due to a lack of knowledge regarding the signals that lead to c-Abl activation and definition of the physiological relevance of the activated c-Abl tyrosine kinase in mammalian cells. A seminal discovery in the PI's laboratory was the finding that c-Abl is activated in response to stimulation of growth factor receptor tyrosine kinases and Src family kinases. Significantly, we have shown that c-Abl plays a functional role in the reorganization of the actin cytoskeleton in response to growth factors. Also, we have demonstrated that engagement of the B cell receptor results in an increase in the levels of cytosolic c-Abl tyrosine kinase activity and binding of the c-Abl SH2 domain to the surface protein CD19 in B cells. Studies in the PI's laboratory have uncovered a family of Abl-interacting (Abi) proteins that bind functionally to c-Abl in vivo and may provide insights into the biological role(s) of the Abl tyrosine kinases. The Abi proteins have been recently implicated in oncogenesis. Abi proteins are targeted for destruction by oncogenic forms of the Abl and Src tyrosine kinases. Moreover, Abi1 is translocated to the MLL gene in acute myeloid leukemia with the t(10;11) chromosomal translocation. Recently, Abi proteins have been implicated in the transduction of signals from Ras to Rac. Like c-Abl, the Abi proteins have been shown to be required for reorganization of the cytoskeleton in response to growth factors.
The specific aims of this proposal are: 1) to define the pathway whereby c-Abl is activated by growth factor receptors, and to elucidate the role of c-Abl in growth factor and Src signaling; and 2) to identify signaling proteins that link c-Abl to cytoskeletal processes such as cell adhesion, spreading and migration. Primarily, the PI will examine the role of the Abi adaptorss in these processes. The availability of mice with targeted deletions of abi-1 and abi-2 will greatly facilitate the elucidation of the functional roles of these adaptors in normal and transformed cells. Deregulation of the c-Abl kinase downstream of constitutively activated forms of receptor kinases, Src family kinases and by mutated Abi proteins may play a role in the development of multiple human cancers. Results from the aims proposed will shed light on the biological role(s) of c-Abl and allow for a better understanding of the pathophysiological consequences of deregulated Abl tyrosine kinase activity in human cancers.
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