Site-specific serine phosphorylation of the IL-3 receptor is required for hemopoietic cell survival
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文摘
The balance between cell survival and death is controlled by transmembrane receptors which upon ligand stimulation undergo phosphorylation and cause downstream activation of anti-apoptotic molecules. In the hemopoietic compartment, a prototypic system undergoing constant cell renewal, IL-3, GM-CSF and IL-5 receptors are major transducers of survival signals, however, the receptor proximal events that determine this vital function have not been defined. We have found that IL-3 stimulation induces phosphorylation of Ser-585 in the common beta chain (bc) of these receptors, and that this event is mediated by cAMP-dependent protein kinase. This promotes the association of phospho-Ser585 of bc with the phosphoserine-binding adaptor protein 14-3-3 and this in turn leads to a cascade of events that activate AKt. Mutation of Ser585 severely impairs this signalling pathway without affecting activation of STAT5, MAPK, JNK or the recruitment of SHP2. Significantly, mutation of Ser585 greatly reduces cell survival in response to IL-3 and promotes apoptosis without affecting entry into the cell cycle or c-myc induction. These results define a distinct IL-3 receptor-mediated survival pathway regulated by site-specific receptor serine phosphorylation and 14-3-3 binding, and suggest that this novel mode of signalling may be utilized by disparate transmembrane receptors that have as a common theme the transduction of survival signals. Site-specific serine phosphorylation of the IL-3 receptor is required for hemopoietic cell survival.