Head, Cell Signaling Section
Genetic Disease Research Branch
National Institutes of Health
49/4A38 National Human Genome Research Institute, National Institutes of Health
Building 49/ 4A38
49 Covent Drive
Bethesda, MD 20892-4472
1999 Searle Scholar
Current Member of the Advisory Board
Roles of Tyrosine Kinases in Osteoclast and T-Cell Signaling Pathways
Dr. Schwartzberg's laboratory studies signal transduction involving cytoplasmic tyrosine kinases and the defects in these pathways that contribute to disease processes. Through a variety of biochemical and genetic techniques, including the generation of transgenic and gene-targeted mice, we seek to determine the normal cellular functions of these molecules and how modulation of their action can lead to treatment for such diverse human diseases as cancer and immunodeficiencies. Our work concentrates on two families of tyrosine kinases, the Src family and the Btk family.
Src is a widely expressed tyrosine kinase, first isolated as a proto-oncogene and subsequently implicated in multiple signaling pathways in normal cells, including responses to growth factor and integrin adhesion receptors. Mutation of Src in mice causes osteopetrosis, resulting from an intrinsic defect in osteoclasts, the cells responsible for bone resorption. Schwartzberg's team has used this physiologically-relevant cell to dissect the function of various domains of Src. Remarkably, they have demonstrated that expression of kinase-inactive Src in transgenic mice can rescue the src-/- phenotype, indicating essential kinase-independent functions for the Src protein. Further mutational analyses suggest that regulation of the SH2 and SH3 protein interaction domains is more critical than the kinase activity of Src itself, particularly in signaling from integrin receptors in response to adhesion. We are continuing our studies of Src concentrating on integrin-mediated signal transduction pathways to identify critical interacting molecules in osteoclasts and other cell-types. These studies have important consequences for Src-based therapeutics, both for bone resorption diseases such as osteoporosis, as well as for tumor treatment. Their results, furthermore, suggest that regions other than the kinase domain play critical roles for the function of protein tyrosine kinases. In a related series of work, they are starting to develop new methods for the delivery of genes to specific cell lineages in bone using retroviral vectors. A wide variety of genetic disease are associated with skeletal malformations, and the ability to dissect the signaling pathways required for normal skeletal development in a mammalian system will be essential to understand these diseases.