Cytokines (interleukins and colony stimulating factors) are involved in the proliferation and maturation of hematopoietic cells and in the regulation of immune responses. These effects are mediated through the high affinity binding of cytokines to specific cell surface receptors. Cloning of the cDNAs encoding cytokine receptors has revealed that most of them display common structural features in their extracellular domain and do not contain kinase consensus sequences in their cytoplasmic region. This rapidly growing cytokine receptor superfamily includes not only hematopoietin receptors but also receptors for growth hormone (GH), prolactin and the ciliary neurotrophic factor (CNTF). Unlike growth factor receptors with intrinsic tyrosine kinase activity, cytokine receptors are often composed of several subunits. Cytokines mediating similar effects on the same target cells have been shown to share a common receptor chain essential for signal transduction. Thus, one receptor subunit is common to the IL3, GM-CSF and IL5 receptors, and the gp130, initially described as the IL6 receptor signal transducing chain, is one of the components of the IL11, LIF, oncostatin and CNTF receptors. Unexpectedly, however, the receptors for cytokines exhibiting different biological activities on T cells like IL2, IL4 and IL7 also share a common chain and inherited mutations of the chain common to these three cytokine receptors are responsible for the human X linked severe combined immunodeficiency syndrome (XSCID). Although none of the cytoplasmic domains of cytokine receptors contains a tyrosine kinase motif, stimulation of target cells with cytokines induces the tyrosine phosphorylation of specific cellular proteins, suggesting that cytoplasmic trysoine kinases interact with cytokine receptors. Several tyrosine kinases of the Src family are known to be activated by cytokine receptors. Binding the Lck to the cytoplasmic domain of the IL2 receptor b chain occurs in a region of the receptor also responsible for Ras activation. However, this region is dispensable for IL2-induced proliferation. More recently, it was shown that cytokines activate tyrosine kinases of the Jak family which interact with a region of the cytokine receptors proximal to the membrane and required for mitogenesis. This family of tyrosine kinases is involved in IFNa and g signal transduction, phosphorylating cytoplasmic transcription factors that translocate to the nucleus and induce the expression of IFN responsive genes. However, cytokines such as erythropoietin, IL3, GH and prolactin, exerting quite different biological activities, all activate the Jak2 kinase. Biological specificity may depend on the substrate specificity of the Jak kinase according to the cell type, on the activation of other unknown Jak kinases or of other tyrosine kinases, and/or on the activation of other signalling pathways such as Ras/MAP kinase, phosphatidyl inositol 3' kinase and their potential substrates.
