SHP2 and SOCS3 Contribute to Tyr-759-dependent Attenuation of Interleukin-6 Signaling through gp130

Abstract

Interleukin-6 (IL-6) activates the Jak/STAT pathway as well as the mitogen-activated protein kinase cascade. Tyrosine 759 of the IL-6 signal-transducing receptor subunit gp130 has been identified as being involved in negative regulation of IL-6-induced gene induction and activation of the Jak/STAT pathway. Because this site is known to be a recruitment motif for the protein-tyrosine phosphatase SHP2, it has been suggested that SHP2 is the mediator of tyrosine 759-dependent signal attenuation. We recently observed that the suppressor of cytokine-signaling SOCS3 also acts through the tyrosine motif 759 of gp130. However, the relative contributions of SHP2 and SOCS3 to the repression of IL-6 signaling are not understood. Therefore, we designed experiments allowing the independent recruitment of each of these proteins to the IL-6-receptor complex. We show that receptor-and membrane-targeted SHP2 counteracts IL-6 signaling independent of SOCS3 binding to gp130. On the other hand, SOCS3 inhibits signaling in cells expressing a truncated SHP2 protein, which is not recruited to gp130. These data suggest, that there are two, largely distinct modes of negative regulation of gp130 activity, despite the fact that both SOCS3 and SHP2 are recruited to the same site within gp130.

Suppressor of Cytokine Signaling-3 Is Recruited to the Activated Granulocyte-Colony Stimulating Factor Receptor and Modulates its Signal Transduction

“…4 The determined affinity is in the same range of the affinity measured in a recent study reporting a K D value of 42 nM for this interaction (32). This difference may be explained by the use of peptides corresponding to the amino acid sequence of human gp130 (pY759 motif (56), amino acid sequence: ␤A-TSSTVQpYSTVVHSG) vs murine gp130 (pY757 motif, Ref. 32, amino acid sequence: acetyl-STASTVEpYSTV VHSG) and, in contrast, by differences in the experimental conditions used in both studies.…”

JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

“…Promoter regions of SOCS1 and SOCS3 genes possess functional STAT binding elements and activation of JAK-STAT signaling induces rapid up-regulation of SOCS proteins by STAT-dependent pathways. In accordance with negative feedback mechanism JAK-STAT signaling is inhibited by SOCS proteins association with catalytic domains of JAKs as well as by SOCS binding to phosphorylated tyrosine residues of cytokine, GH, Prl, leptin, and erythropoietin (Epo) receptors which act as docking sites for downstream signaling [18][19][20] . STAT activation can also be inhibited by direct interaction with protein inhibitors of activated STAT proteins (PIAS) [21] .…”

“…There is reciprocal negative regulation of JAK-STAT3 and MAPK signaling by IL-6 [15,101,102] . SOCS3 activated by STAT3 suppresses IL-6 signaling [15,[18][19][20] .…”

General Nature of the STAT3-Activated Anti-Inflammatory Response

“…Yoshimura and colleagues (33)(34)(35)(36) have shown that IL-6 signaling in SOCS3-deficient macrophages allows the IL-6R to generate an AIR-like inhibitory signal following LPS stimulation. SOCS3 is an inducible E3 ligase that binds to Y757 in gp130 (Fig.…”