SH2 domain and a C-terminal SOCS box. The N-terminal New York, New York 10032 regions of these proteins are highly variable (Figure 1). Table 1 summarizes different nomenclatures that have been used in the literature for these proteins. In addition The growth, differentiation, and function of hematopoi- to the SH2-containing members, there are at least a etic cells are controlled by the coordinated action of dozen other proteins that share the SOCS box motif but the cytokine network. The pathways by which cytokines not the SH2 domain (Hilton et al., 1998). Instead, these exert their biologic effects have been under intensive proteins possess other domains that can potentially investigation over the past few years. As most cytokine mediate protein-protein interactions. Together, these receptors lack a cytoplasmic kinase domain, ligand- twenty proteins form a superfamily of proteins that may dependent tyrosine phosphorylation is mediated by require the SOCS box for their function. The non-SH2-nonreceptor tyrosine kinases. The major tyrosine ki- containing proteins can be further divided into several nasesactivatedimmediatelyfollowingcytokinestimula- subfamilies: WSB for WD-40-repeat-containing protion are the Janus kinase (JAK) family. In fact, the JAK- teins, SSB for SPRY domain-containing proteins, and STAT pathway is one of the most important mechanisms ASB for ankyrin-repeat-containing proteins. In addition, by which many cytokines activate gene transcription. there are two small GTPases and two ESTs of unknown When cytokines bind to receptors on the cell surface, structural class that contain the SOCS box motif they cause receptor oligomerization, which in turn in-(Figure 1). duces JAK kinase activation. The activated JAK kinases, in turn, phosphorylate the cytokine receptors, leading CIS: Prototype of the SOCS Family Proteins to the recruitment and subsequent activation of other The first member of the SOCS family was identified as signaling molecules such as the STAT family proteins. an immediate early gene induced in response to several TheactivatedSTATproteinstranslocateintothenucleus cytokines (Yoshimura et al., 1995). It was denoted as and activate transcription of a range of cytokine respon- CIS for cytokine-inducible SH2-containing protein. CIS sive genes. has been shown to bind to phosphorylated tyrosines on Although it is clear that the effect of most cytokines is multiple cytokine receptors. In vitro and in vivo studies limited in both magnitude and duration, the mechanisms support a role for CIS as a negative regulator of STAT5 underlying this regulation are not well understood. The activation in response to several cytokines, including most important limitation of cytokine activity occurs EPO, IL-2, and IL-3 (for review, see Yasukawa et al., through regulated production of the cytokine itself. In 2000). One mechanism by which CIS may inhibit cytoaddition, several other mechanisms have been demon- kine signaling is by competing for Stat5 binding sites strated to control responsiveness to cytokines. Among on the activated receptors and thus preventing recruitthese, selective expression of cytokine receptors has ment of Stat5 to the receptors (Figure 2). Alternatively, been well documented as an effective way to regulate CIS may function as an adaptor protein linking cytokine cytokine responsiveness. In addition, more complex receptors and other negative regulators. Matsumoto et regulation exists inside the cells, where signals from al.(1999) generated transgenic mice expressing CIS unmultiple stimuli converge. Intracellular regulation can dercontrolofthe-actin promoter. Mice overexpressing occur on the receptor at the …