SOCS Proteins, Regulators of Intracellular Signaling

The growth, differentiation, and function of hematopoietic cells are controlled by the coordinated action of the cytokine network. The pathways by which cytokines exert their biologic effects have been under intensive investigation over the past few years. As most cytokine receptors lack a cytoplasmic kinase domain, ligand-dependent tyrosine phosphorylation is mediated by nonreceptor tyrosine kinases. The major tyrosine kinases activated immediately following cytokine stimulation are the Janus kinase (JAK) family. In fact, the JAK-STAT pathway is one of the most important mechanisms by which many cytokines activate gene transcription. When cytokines bind to receptors on the cell surface, they cause receptor oligomerization, which in turn induces JAK kinase activation. The activated JAK kinases, in turn, phosphorylate the cytokine receptors, leading to the recruitment and subsequent activation of other signaling molecules such as the STAT family proteins. The activated STAT proteins translocate into the nucleus and activate transcription of a range of cytokine responsive genes. Although it is clear that the effect of most cytokines is limited in both magnitude and duration, the mechanisms underlying this regulation are not well understood. The most important limitation of cytokine activity occurs through regulated production of the cytokine itself. In addition, several other mechanisms have been demonstrated to control responsiveness to cytokines. Among these, selective expression of cytokine receptors has been well documented as an effective way to regulate cytokine responsiveness. In addition, more complex regulation exists inside the cells, where signals from multiple stimuli converge. Intracellular regulation can occur on the receptor at the plasma membrane, in the cytoplasm, and in the nucleus. Tyrosine phosphatases have been reported to modulate signaling by dephosphorylation of signaling proteins. The PIAS family of proteins has also been implicated in the negative regulation of STAT function.