Biomedical Sciences Graduate Program | University of California, San Francisco

Our laboratory studies the role of cytoplasmic tyrosine kinases in leukocyte responses to extracellular stimuli, such as growth factors, cytokines, chemokines and adhesion. Using transgenic and knockout mouse models, we have focused on studies involving the Src-family and Syk tyrosine kinases. Deficiency in these kinases blocks leukocyte integrin signaling responses, resulting in a failure of cells to respond to adhesive stimuli. As a result, neutrophils and macrophages from these mice fail to adhere or respond to extra-cellular matrix coated surfaces. In culture, this results in defective leukocyte respiratory burst/degranulation responses and in vivo animals fail to mount appropriate inflammatory responses. The cellular defect caused by lack of these kinases appears to involve regulation of actin cytoskeletal dynamics following adhesion. Studies of signaling pathways suggest that Src-family and Syk kinases act in a linear pathway leading to immune activation. In contrast to their role in adhesion, deficiency of Src-family kinases also results in a paradoxical increase in chemokine signaling reactions. This results in an increased chemotatic response as well in enhanced intracellular signaling to chemokine stimulation. These observations demonstrate that Src-kinases play a dual role in leukocyte physiology, regulating both positive and negative signaling pathways. Future studies are focused on dissecting the integrin-dependent signaling pathways regulated by these kinases: how do the kinases detect adhesion-receptor engagement and what intracellular molecules are they interacting with? Methods used include retroviral reconstitution of hematopoietic stem cells along with bone marrow/fetal liver transplantation. Effort is directed towards elucidating the mechanism by which these kinases negatively regulate the chemokine pathway. Additional studies of these kinases in dendritic cell maturation/function are ongoing as well as experiments examining the effect of these mutations on overall immune response to infection/inflammation. An additional project in the lab involves studies of the contribution of cytoplasmic tyrosine kinases to leukemia pathogenesis in transgenic murine models. Animals with mutations affecting other aspects of myeloid leukocyte function are being generated.