Twenty proteins containing a C-terminal SOCS box form five structural classes

Abstract

The four members of the recently identified suppressor of cytokines signaling family (SOCS-1, SOCS-2, SOCS-3, and CIS, where CIS is cytokine-inducible SH2-containing protein) appear, by various means, to negatively regulate cytokine signal transduction. Structurally, the SOCS proteins are composed of an N-terminal region of variable length and amino acid composition, a central SH2 domain, and a previously unrecognized C-terminal motif that we have called the SOCS box. By using the SOCS box amino acid sequence consensus, we have searched DNA databases and have identified a further 16 proteins that contain this motif. These proteins fall into five classes based on the protein motifs found N-terminal of the SOCS box. In addition to four new SOCS proteins (SOCS-4 to SOCS-7) containing an SH2 domain and a SOCS box, we describe three new families of proteins that contain either WD-40 repeats (WSB-1 and -2), SPRY domains (SSB-1 to -3) or ankyrin repeats (ASB-1 to -3) N-terminal of the SOCS box. In addition, we show that a class of small GTPases also contains a SOCS box. The expression of representative members of each class of proteins differs markedly, as does the regulation of expression by cytokines. The function of the WSB, SSB, and ASB protein families remains to be determined.Cytokines act by binding to and inducing dimerization of members of the hemopoietin receptor family expressed on the surface of responsive cells (1). Although the cytoplasmic proteins that then transduce the signal are relatively welldefined and include the Janus kinase (JAK) family of kinases and signal transducers and activators of transcription (STAT) transcription factors (2, 3), the proteins involved in limiting signal transduction are not well characterized.The four known members of the suppressor of cytokine signaling (SOCS) family (CIS, SOCS-1͞SSI-1͞JA B-1, SOCS-2, and SOCS-3, where CIS is cytokine-inducible SH2-containing protein) represent a family of negative regulators of cytokine signal transduction (4-9). The SOCS proteins appear to form part of a classical negative feedback loop that regulates cytokine signal transduction. Transcription of each of the SOCS genes occurs rapidly in vitro and in vivo in response to cytokines, and once produced, the various members of the SOCS family appear to inhibit signaling in different ways. For SOCS-1, inhibition of signal transduction appears to occur by binding to and inhibiting the catalytic activity of members of the JAK family of cytoplasmic kinases (4-6), while CIS appears to act by competing with signaling molecules such as the STATs for binding to phosphorylated receptor cytoplasmic domains (7, 9).The SOCS proteins share structural similarities. Each has an N-terminal region of variable length and highly variable amino acid sequence, a central SH2 domain, and a striking region of C-terminal homology that we designated the SOCS box (4). Given the sequence similarity evident in the SOCS box of the four SOCS proteins and its conserved position at the C terminus of each protein, ...

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