Interleukin-3 (IL-3) is a multipotential hematopoietic growth factor that mediates its growth and differentiation effects on target cells by binding to a specific surface membrane receptor. The mechanism(s) involved in triggering and sustaining the transmembrane signal(s) generated by this interaction is central to the issue of normal and probably abnormal hematopoietic cell growth. Our recent studies on the biochemical characterization of the IL-3 receptor and elucidation of certain protein phosphorylation mechanism(s) possibly involved in receptor mediated transmembrane signalling have allowed me to formulate an experimentally testable model. The model features sequential activation events beginning with specific binding of IL-3 to its surface receptor to initiate immediate tyrosine phosphorylation of a Mr 140 kDa receptor component followed by the rapid tyrosine and serine phosphorylation and enzymatic activation of c-raf and possibly PKC, two cytosolic ser/thr protein kinases we have found to be involved in regulation of IL-3 growth. In order to critically examine and test this model, studies will focus on cloning the high affinity IL-3 receptor as well as continued biochemical characterization of the IL-3 receptor. These will include studies designed to understand the molecular mechanism(s) and consequences of ligand-induced tyrosine and serine protein phosphorylations of the specific functional substrates, c-raf and PKC. By cloning and analyzing the IL-3 receptor as well as dissecting the specific initial transmembrane signals generated as a result of ligand binding, I will be able to better understand the nature of growth regulation in hematopoietic cells, both normal and abnormal.
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