The fundamental cellular processes of proliferation, differentiation, and apoptosis are under control by polypeptide and lipid factors. Ligand-activated cytosolic protein tyrosine kinases (PTK) regulate these responses. PTKs play a central role in the functioning of leukocytes, which mediate inflammation and tissue injury, and platelets, which direct hemostasis and tissue injury. Multiple tyrosine kinases exist in any particular cell. A very important problem in cell biology is to attribute a specific function(s) to a specific kinase. A wide range of cytokines lead to the tyrosine phosphorylation of one of the Jak-related PTK, and current dogma holds that the Jaks are the principal signalling PTK for cytokine receptors. However, the investigator's have identified Lyn as a rapidly activated signalling molecule for granulocyte macrophage colony-stimulating factor (G-CSF), two important growth factors for white blood cell development. Lyn is a member of the Src family of protein tyrosine kinases. More recent studies in their laboratory with wild-type B cells and their mutagenized lyn- deficient cell lines, which have been stably transfected with the human G- CSF receptor, have shown that G-CSF's induction of DNA synthesis requires Lyn and that the activation of Jak1 of Jak2 is not sufficient for that response. They hypothesize that Lyn and Jak2 direct different pathways for leukocyte proliferation and apoptosis.
The specific aims of this application are 1) Determine the structural mechanisms whereby Lyn and Jak2 interact with the G-CSFR, 2) Define the relative contributions of Lyn and Jak2 in leukocyte signalling by transfecting cells with their dominant negative forms and by analyzing the effects of lyn-deficiency on G-CSF signalling in proliferation and apoptosis and 3) identify Lyn-specific and Jak2-specific signalling partners in leukocytes by the yeast two-hybrid system. Two long-term goals are to understand the molecular defects in hypo- and hyper-proliferative white blood cell disorders and to develop drugs based on protein tyrosine kinase signalling pathways to interrupt leukocyte activation. This NIH K02 award will permit the applicant to supplement his American Cancer Society independent investigator grants and protect his laboratory time to at least 85%, this will solidify his establishment as an independent scientist.
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