Genetic and Biochemical Approaches to Tyrosine Kinase Function

Human Genome Research

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Abstract

Our laboratory studies the functions of non-receptor tyrosine kinases, molecules required for intracellular signaling pathways involved in normal cellular growth and differentiation as well as abnormal growth and development involved in the formation and progression of cancer. We apply a combination of mouse genetics, cellular biology and protein biochemistry to the study of these molecules. Our work has concentrated on how these molecules contribute to normal function of cells of the immune system and the skeletal system and how lessons we learn from these systems can be extended to other celltypes in which these molecules function. Our recent work has concentrated on studies of the Btk family of kinases. Btk has previously been shown to be required for normal function of B cells and mutation of Btk is responsible for the human genetic disorder X-linked agammmaglobulimemia. We have recently shown that mutation of other Btk family kinases can severely impair T lymphocyte function in mice, thereby establishing for the first time a role for these kinases in T cell mediated immune responses. In particular, we have demonstrated that mutation of two Btk family kinases, Rlk and Itk leads to marked defects in T cell responses to stimulation in culture and to infectious agents in the animal. We have also continued work on the study of Src family kinases in bone cell function. We have recently shown that expression of a truncated mutant of Src can act as a dominant-negative molecule and lead to programmed cell death or apoptosis. We have extended this work to show that this mutant can alter cell survival pathways required for angiogenesis and tumor growth. Recent work has demonstrated that the SH2 (Src homology 2) domain is important for these cell survival pathways. This work provides a model for the use of inhibitors of Src function in the treatment of certain tumors. - Genetics, Immunology, Infectious Diseases, Tropical Diseases, Osteoporosis