Interaction of Human Suppressor of Cytokine Signaling (SOCS)-2 with the Insulin-like Growth Factor-I Receptor

Abstract

A family of proteins has recently been reported to function in a negative feedback loop to regulate signaling by cytokine receptors via the JAK 1 (Janus kinase)/STAT(signal transducer and activator of transcription) pathway (1-9). The first member of this family to be reported was mouse CIS (cytokine inducible SH2-containing protein) (1). Upon binding of ligand to cytokine receptors, receptor-associated JAKs become activated and phosphorylate tyrosine residues on the membrane distal portion of the receptor (10). Signaling molecules which subsequently bind to these phosphotyrosine containing motifs on the receptor include members of the STAT family. STATs are phosphorylated by cytokine receptor-associated JAKs, form dimers, and travel to the nucleus where they activate transcription. CIS was isolated as a cytokine responsive immediateearly gene in mouse hematopoietic cells (1, 2). CIS mRNA encodes a polypeptide of 257 amino acids that contains an SH2 domain in the middle of the molecule. Expression of CIS in IL-3-dependent hematopoietic cell lines reduced the growth rate of the transformants, suggesting a negative role of CIS in signal transduction. The CIS protein associated with tyrosinephosphorylated erythropoietin (EPO) receptor and the tyrosine-phosphorylated ␤ chain of the IL-3 receptor, presumably by binding of the CIS SH2 domain to phosphotyrosine containing motifs in the receptors. A mutant IL-2 receptor that failed to activate STAT5 could not induce CIS, suggesting that STAT5 was important for cytokine induction of CIS. Indeed, upstream of the transcription initiation site in the CIS promoter are four potential STAT5-binding sites. Expression of STAT5 and the EPO receptor in HEK293 cells conferred EPOdependent activation of the CIS promoter. In these cells, EPOdependent tyrosine phosphorylation of STAT5 was suppressed when CIS was coexpressed. Taken together, these results provide evidence for a negative feedback loop in which CIS is induced by the cytokine and then binds to the cytokine receptor, preventing the activation of STAT by JAKs (1, 2). Subsequently, three CIS-related proteins were described and these proteins have been designated as SSI (STAT-induced STAT inhibitor) or SOCS (suppressor of cytokine signaling) proteins 1-3 (3-7, 9). Together with CIS, SSI/SOCS proteins share a common domain structure consisting of an NH 2 -terminal region of variable length, a central SH2 domain and a COOHterminal motif, termed the SOCS box, of unknown function. In contrast to cytokine receptors which do not have intrinsic tyrosine kinase activity but utilize JAKs for receptor phosphorylation and phosphorylation of downstream signaling molecules such as STATs, the insulin-like growth factor I (IGF-I) receptor is a member of the tyrosine kinase family of growth factor receptors (11,12). The IGF-I receptor is important for cellular growth, differentiation, and inhibition of apoptosis. Binding of IGF-I or IGF-II to the IGF-I receptor results in receptor autophosphorylation. Receptor autophosphorylation amplifies t...

SOCS proteins in regulation of receptor tyrosine kinase signaling

“…SOCS1 is also known to interacts with activated MET [32] and AXL [33] and to block hepatocyte growth factor-induced MET, GAB1 and ERK1/2 phosphorylation [32]. SOCS1 has been shown in a yeast two-hybrid assay to associate with insulin-like growth factor 1 (IGF1) receptor (IGF1R) [34] but its role in IGF1 signaling has not yet been defined.…”

“…SOCS2 negatively regulates the GH receptor through ubiquitination-dependent degradation [43]. SOCS2 was also found to interact with IGF1R and INSR, and this interaction occurred only when the receptor was activated [34,44] suggesting that similar to SOCS1 the interaction between receptor and SOCS2 is mediated through receptor phosphotyrosine residues and the SOCS2 SH2 domain. Despite this, there is no evidence that SOCS2 can regulate the activity of the insulin or the IGF1 receptor.…”

“…The interaction between FLT3 and SOCS2 is mediated through phospho-tyrosine residues Y589 and Y919 in FLT3 and the SOCS2 SH2 domain. Unlike the IGF1R, FLT3 mediates tyrosine phosphorylation of SOCS2 [16,34]. Thus, the SOCS2 SH2 domain displays a higher degree of selectivity in its interaction and is phosphorylated only by selected receptor.…”

SOCS2 Induces Neurite Outgrowth by Regulation of Epidermal Growth Factor Receptor Activation

“…There are eight known members of the SOCS gene family (SOCS1-7 and CIS), which are expressed in different tissues, induced by different groups of cytokines, and regulate different Janus-activated kinase/STAT pathways (8). However, various members of the SOCS family have also been shown to interact with signal transduction pathways not associated with the Janus-activated kinase/STAT pathway, such as the receptor tyrosine kinases insulin-like growth factor receptor (9,10) and Kit (11). They have also been reported to interact with the GTPase-activating protein p120 RasGAP to enhance Ras activation (12) and the guanine nucleotide exchange factor Vav (11,13).…”

Suppressor of Cytokine Signaling 6 Associates with KIT and Regulates KIT Receptor Signaling

“…SOCS1 binds to KIT, FLT3 (29), and FMS (30). SOCS2 binds to the insulin-like growth factor receptor (31). SOCS1 and SOCS3 bind to EGFR and may down-regulate activation of STATs by EGFR (32).…”