SOCS/CIS Protein Inhibition of Growth Hormone-stimulated STAT5 Signaling by Multiple Mechanisms

Ram, Prabha A.; Waxman, David J.

doi:10.1074/jbc.274.50.35553

Cited by 338 publications

(280 citation statements)

References 55 publications

(104 reference statements)

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“…Regulation of STAT5 activation by SOCS2 has also been demonstrated in overexpression studies, although it is not as potent as other SOCS family members, such as SOCS1 and SOCS3 (32). Although the precise mechanism by which SOCS2 regulates STAT5 activation downstream of GH signaling remains to be determined, it appears to involve SOCS2 competitively binding to the STAT5 and SHP2 binding sites on the GH receptor (18,32,33). Here we show that SOCS2 can also inhibit STAT5 activation independently of GH stimulation.…”

Section: Discussionmentioning

confidence: 71%

“…In addition, activation of both STAT5a and STAT5b is moderately prolonged in cells from these mice in response to GH, due to their inability to effectively down-regulate the activation (27). Regulation of STAT5 activation by SOCS2 has also been demonstrated in overexpression studies, although it is not as potent as other SOCS family members, such as SOCS1 and SOCS3 (32). Although the precise mechanism by which SOCS2 regulates STAT5 activation downstream of GH signaling remains to be determined, it appears to involve SOCS2 competitively binding to the STAT5 and SHP2 binding sites on the GH receptor (18,32,33).…”

Section: Discussionmentioning

confidence: 95%

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

Goldshmit

Walters

Scott

et al. 2004

Journal of Biological Chemistry

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Suppressor of cytokine signaling (SOCS) 2 is a negative regulator of growth hormone (GH) signaling that regulates body growth postnatally and neuronal differentiation during development. SOCS2 binds to the GH receptor and inhibits GH signaling, including attenuation of STAT5 activation. Here we describe a new function and mechanism of action for SOCS2. Overexpression of SOCS2 in central nervous system neurons promoted neurite outgrowth, and in PC12 cells, neurite outgrowth was induced under nondifferentiating conditions, leading to inhibition of the neurite-inhibitory GTPase Rho and activation of the neurite-promoting GTPase Rac1. Addition of the epidermal growth factor receptor (EGFR) inhibitors PP3 or AG490 or the Src kinase inhibitor PP2 blocked the SOCS2-induced neurite outgrowth. The overexpressed SOCS2 bound to the EGFR, which was constitutively phosphorylated at Tyr 845 , the Src binding site. Overexpression of the phosphatase SHP-2 reduced the constitutive EGFR phosphorylation and subsequent neurite outgrowth. SOCS2 expression also resulted in a modest 30% decrease in phosphorylation of STAT5b at Tyr 699 , which is the primary site on STAT5 phosphorylated by GH; however, total tyrosine phosphorylation of STAT5 was decreased by 75-80% under basal and epidermal growth factorstimulated conditions. Our findings suggest that SOCS2 regulates EGFR phosphorylation, leading to regulation of neurite outgrowth through a novel pathway that is distinct from GH.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 95%

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

Goldshmit

Walters

Scott

et al. 2004

Journal of Biological Chemistry

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“…Members of the SOCS protein family have been shown to regulate GH signaling in vitro through multiple mechanisms involving all three SOCS functional domains (24). For example, SOCS1 can inhibit JAK2 through either its N-terminal kinase inhibitory region or SH2 domains and also mediate its degradation by means of the SOCS box (17).…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of the SOCS2–elongin C–elongin B complex defines a prototypical SOCS box ubiquitin ligase

Bullock

Debreczeni

Edwards

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

146

155

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Growth hormone (GH) signaling is tightly controlled by ubiquitination of GH receptors, phosphorylation levels, and accessibility of binding sites for downstream signaling partners. Members of the suppressors of cytokine signaling (SOCS) family function as key regulators at all levels of this pathway, and mouse knockout studies implicate SOCS2 as the primary suppressor. To elucidate the structural basis for SOCS2 function, we determined the 1.9-Å crystal structure of the ternary complex of SOCS2 with elongin C and elongin B. The structure defines a prototypical SOCS box ubiquitin ligase with a Src homology 2 (SH2) domain as a substrate recognition motif. Overall, the SOCS box and SH2 domain show a conserved spatial domain arrangement with the BC box and substrate recognition domain of the von Hippel-Lindau (VHL) tumor suppressor protein, suggesting a common mechanism of ubiquitination in these cullin-dependent E3 ligases. The SOCS box binds elongin BC in a similar fashion to the VHL BC box and shows extended structural conservation with the F box of the Skp2 ubiquitin ligase. A previously unrecognized feature of the SOCS box is revealed with the burial of the C terminus, which packs together with the N-terminal extended SH2 subdomain to create a stable interface between the SOCS box and SH2 domain. This domain organization is conserved in SOCS1-3 and CIS1, which share a strictly conserved length of their C termini, but not in SOCS4, 5, and 7, which have extended C termini defining two distinct classes of inter-and intramolecular SOCS box interactions.growth hormone receptor ͉ cytokine signaling T he growth hormone (GH) signaling pathway is the main regulator of longitudinal growth in mammals, and it stimulates differentiation and mitogenesis and modulates lipid, nitrogen, and mineral metabolism. Signaling from the GH receptor (GHR) is initiated by GH-induced dimerization followed by Janus kinase (JAK) 2 crossphosphorylation and subsequent phosphorylation of signal transducers and activators of transcription (STATs) (in particular, STAT5b). Phosphorylated STAT5 dimerizes and enters the nucleus, where it initiates transcription of insulin-like growth factor (IGF) I, IGFBP3, suppressors of cytokine signaling (SOCS) 1-3, CIS, and other target genes (recently reviewed in ref. 1). The duration of the GHR signal is a key determinant of the biological response. The signal is attenuated by many regulatory mechanisms, including ubiquitin-dependent receptor internalization and degradation (see, for example, ref. 2), cleavage by TACE (TNF-␣-converting enzyme) (3), tyrosine dephosphorylation of receptors and associated JAK kinases (4), and SOCS.The SOCS family comprises SOCS1-7 and CIS1, of which SOCS1-3 and CIS1 have been shown to regulate GH signaling in vitro (1). The role of SOCS2 in GH signaling in vivo has been convincingly demonstrated, as displayed by the phenotype of SOCS2-deficient mice, which are 30-40% larger than normal littermates (5). This phenotype is similar to mice overexpressing GH (6) and high growth (hg) ...

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“…Indeed, SOCS-3 binds to the tyrosine-phosphorylated IL-2␤ receptor (6) and to the growth hormone receptor (41,42). An association between a receptor tyrosine kinase and SOCS has previously been observed.…”

Section: Socs-3 As a Negative Regulator Of Insulin Signalingmentioning

confidence: 99%

SOCS-3 Is an Insulin-induced Negative Regulator of Insulin Signaling

Emanuelli¹,

Peraldi²,

Filloux³

et al. 2000

Journal of Biological Chemistry

400

284

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The SOCS proteins are induced by several cytokines and are involved in negative feedback loops. Here we demonstrate that in 3T3-L1 adipocytes, insulin, a hormone whose receptor does not belong to the cytokine receptor family, induces SOCS-3 expression but not CIS or SOCS-2. Using transfection of COS-7 cells, we show that insulin induction of SOCS-3 is enhanced upon Stat5B expression. Moreover, Stat5B from insulin-stimulated cells binds directly to a Stat element present in the SOCS-3 promoter. Once induced, SOCS-3 inhibits insulin activation of Stat5B without modifying the insulin receptor tyrosine kinase activity. Two pieces of evidence suggest that this negative regulation likely results from competition between SOCS-3 and Stat5B binding to the same insulin receptor motif. First, using a yeast two-hybrid system, we show that SOCS-3 binds to the insulin receptor at phosphotyrosine 960, which is precisely where Stat5B binds. Second, using confocal microscopy, we show that insulin induces translocation of SOCS-3 from an intracellular compartment to the cell membrane, leading to colocalization of SOCS-3 with the insulin receptor. This colocalization is dependent upon phosphorylation of insulin receptor tyrosine 960. Indeed, in cells expressing an insulin receptor mutant in which tyrosine 960 has been mutated to phenylalanine, insulin does not modify the cellular localization of SOCS-3. We have thus revealed an insulin target gene of which the expression is potentiated upon Stat5B activation. By inhibiting insulin-stimulated Stat5B, SOCS-3 appears to function as a negative regulator of insulin signaling.

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SOCS/CIS Protein Inhibition of Growth Hormone-stimulated STAT5 Signaling by Multiple Mechanisms

Cited by 338 publications

References 55 publications

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

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

Crystal structure of the SOCS2–elongin C–elongin B complex defines a prototypical SOCS box ubiquitin ligase

SOCS-3 Is an Insulin-induced Negative Regulator of Insulin Signaling

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