The overall aim of this application is the molecular and functional characterization of a novel receptor-initiated signaling pathway we have identified in hematopoietic cells. Activation of this pathway is triggered by engagement of the GM-CSF/IL-3/IL-5 receptors in myeloid cells and of the GPIb-IX-V receptor complex in platelets. A unique feature of this pathway is its initiation by receptor site-specific serine phosphorylation and recruitment of phosphoserine-binding adaptor protein 14-3-3.
The specific aims of this proposal are to: 1. Biochemically characterize the interactions between receptors, 14-3-3 and PI 3-kinase seeking to determine the assemblage and architecture of these complexes. 2. Determine the functional significance of these complexes in myeloid cells and platelets in vitro. 3. Determine the functional significance of this pathway in vivo using specific animal models. This proposal has the long-term aim of understanding the mechanism of activation of myeloid cells and platelets, two hematopoietic cell types essential for a living organism. In the case of myeloid cells, these studies have the potential to unravel the poorly understood survival and """"""""primary"""""""" effects of GM-CSF, IL-3 and IL-5, which the body utilizes to combat invading pathogens. In platelets, these studies should provide essential knowledge on the activation of the receptor GPIb-IX-V complex and its role in maintaining homeostasis. Importantly, activation of the novel signaling pathway we have uncovered is likely to be involved in debilitating human pathologies and its characterization may provide novel targets for interfering with its assemblage for therapeutic purposes. In myeloid cells, abnormal activation of the GM-CSF, IL-3 and IL-5 receptors has been implicated in myeloid leukaemias and chronic inflammatory diseases such as asthma and rheumatoid arthritis. In platelets, abnormal activation of the GPIb-LX-V complex is involved in thrombosis that triggers unstable angina, myocardial infarction and stroke, the leading combined causes of death in the western world.
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