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

Abstract

Suppressor of cytokine signaling (SOCS) proteins are a family of Src homology 2-containing adaptor proteins. Cytokine-inducible Src homology domain 2-containing protein, SOCS1, SOCS2, and SOCS3 have been implicated in the down-regulation of cytokine signaling. The function of SOCS4, 5, 6, and 7 are not known. KIT receptor signaling is regulated by protein tyrosine phosphatases and adaptor proteins. We previously reported that SOCS1 inhibited cell proliferation in response to stem cell factor (SCF Cytokines and growth factors regulate the survival, proliferation, differentiation, and migration of hematopoietic cells. Binding of these factors to transmembrane receptors induces receptor activation, which in turn results in the recruitment of signaling complexes in the vicinity of the plasma membrane. The kinetics and magnitude of signal transduction are tightly regulated by multiple mechanisms. Among proteins that modulate signaling, members of the suppressor of cytokine signaling (SOCS) 1 family have been shown to down-regulate the function of cytokines or growth factors (1-3).The eight members of the SOCS family, SOCS1-7 and CIS (cytokine-inducible Src homology domain (SH2)-containing protein), are structurally characterized by a SH2 domain followed by a conserved C-terminal motif, the SOCS box (4). The N-terminal region of SOCS proteins is variable both in length and in the primary amino acid sequence. Although many reports including knock-out studies shed light on the function of CIS (5, 6), SOCS1 (7, 8), SOCS2 (9, 10), and SOCS3 (11-13), very little is known regarding the function of SOCS4, SOCS5, SOCS6, and SOCS7.The mechanisms whereby CIS, SOCS1, and SOCS3 inhibit signaling by classical cytokine receptor (i.e. receptors without catalytic activity that associate with JAK tyrosine kinases) are the best characterized. All three are involved in the downregulation of the JAK/STAT pathway. SOCS1 has a dual function as a direct potent JAK kinase inhibitor (14 -17) and as a component of an E3 ubiquitin-ligase complex recruiting substrates to the protein degradation machinery (18 -20). SOCS3 also inhibits JAK activity but indirectly through recruitment to the cytokine receptors (1, 21). More recently, SOCS3 has been suggested to compete with SHP2 for the same binding sites on glycoprotein 130 (22, 23), erythropoietin receptor (21), and leptin receptor (24). CIS binds to cytokine receptors at STAT5-docking sites, which impairs recruitment of STAT5 to the receptor signaling complex and results in the down-regulation of STAT5 activation (6,25).Mice lacking SOCS6 have been generated, and they developed normally with the exception of a 10% reduction in weight compared with wild-type littermates (26). SOCS6 mRNA was induced by erythropoietin in cell lines (27) and was ubiquitously expressed in murine tissues (26). SOCS6 does not interact with JAKs, but the interaction with elongins B and C suggests that, as all SOCS proteins, it might be part of an E3 ubiquitin-ligase complex (28). Yet, there is no evidence so far suggesti...

SOCS proteins in regulation of receptor tyrosine kinase signaling

“…SOCS proteins display a degree of specificity for the different receptors. It has been shown that KIT associates with SOCS6 and weakly interacts with SOCS4 and SOCS5 but not with SOCS2 and SOCS3 [18]. Thus, SOCS family proteins appear to be important components that regulate RTK signaling ( Table 2).…”

“…SOCS2 has been reported to associate with both wild-type and oncogenic FLT3 but not with KIT [16,18]. The interaction between FLT3 and SOCS2 is mediated through phospho-tyrosine residues Y589 and Y919 in FLT3 and the SOCS2 SH2 domain.…”

“…Although SOCS4 associates with EGFR through a specific phosphotyrosine residue, SOCS4-mediated EGFR degradation was independent of EGF stimulation, probably due to the constitutive activity of the EGFR in the overexpression system used in the study. Besides regulation of EGFR signaling, SOCS4 weakly associates with KIT but its role in KIT signaling remains to be defined [18].…”

“…Furthermore, SOCS5 associates following growth factor stimulation with Shc1 at pY317 through its SH2 domain [62] suggesting that SOCS5 not only limits receptor stability but also induces degradation of downstream signaling proteins. SOCS5 also weakly associates with KIT but its role in KIT regulation has not been studied [18].…”

“…The KIR motif can inhibit kinase activity by impairing access to substrates, while the SH2 domain can competitively inhibit the binding of other proteins to phosphotyrosine residues. The interactions between RTKs and SOCS have been shown to be selective, occurring only with the ligand-stimulated wild-type receptors or with constitutively active mutant receptors [16][17][18].…”