Cytokine receptor signaling through the Jak–Stat–Socs pathway in disease

O’Sullivan, Lynda A.; Liongue, Clifford; Lewis, Rowena S.; Stephenson, Sarah E. M.; Ward, Alister C.

doi:10.1016/j.molimm.2006.11.025

Cited by 276 publications

(225 citation statements)

References 99 publications

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“…Since JAK-1 pairs with JAK-3 in all ␥-chain receptor-mediated signaling pathways (24), inhibitors of JAK-3 that also inhibit JAK-1 may exhibit increased cellular potency. However, JAK-1 inhibition will also interfere with signaling pathways mediated by other cytokines, such as the gp130 receptor cytokines (IL-6 family) and the cytokine type II receptors such as the IFNs and the IL-10 family (38).…”

Section: Discussionmentioning

confidence: 99%

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Lin

Hegen

Quadros

et al. 2010

Arthritis & Rheumatism

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Objective. All ␥-chain cytokines signal through JAK-3 and JAK-1 acting in tandem. We undertook this study to determine whether the JAK-3 selective inhibitor WYE-151650 would be sufficient to disrupt cytokine signaling and to ameliorate autoimmune disease pathology without inhibiting other pathways mediated by JAK-1, JAK-2, and Tyk-2.Methods. JAK-3 kinase selective compounds were characterized by kinase assay and JAK-3-dependent (interleukin-2 [IL-2]) and -independent (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]) cell-based assays measuring proliferation or STAT phosphorylation. In vivo, off-target signaling was measured by IL-22-and erythropoietin (EPO)-mediated models, while on-target signaling was measured by IL-2-mediated signaling. Efficacy of JAK-3 inhibitors was determined using delayed-type hypersensitivity (DTH) and collagen-induced arthritis (CIA) models in mice.Results. In vitro, WYE-151650 potently suppressed IL-2-induced STAT-5 phosphorylation and cell proliferation, while exhibiting 10-29-fold less activity against JAK-3-independent IL-6-or GM-CSF-induced STAT phosphorylation. Ex vivo, WYE-151650 suppressed IL-2-induced STAT phosphorylation, but not IL-6-induced STAT phosphorylation, as measured in whole blood. In vivo, WYE-151650 inhibited JAK-3-mediated IL-2-induced interferon-␥ production and decreased the natural killer cell population in mice, while not affecting IL-22-induced serum amyloid A production or EPO-induced reticulocytosis. WYE-151650 was efficacious in mouse DTH and CIA models.Conclusion. In vitro, ex vivo, and in vivo assays demonstrate that WYE-151650 is efficacious in mouse CIA despite JAK-3 selectivity. These data question the need to broadly inhibit JAK-1-, JAK-2-, or Tyk-2-dependent cytokine pathways for efficacy.

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Section: Discussionmentioning

confidence: 99%

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Lin

Hegen

Quadros

et al. 2010

Arthritis & Rheumatism

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“…SOCS proteins compete with STATs for binding sites on the receptor by SH2 domains (8). In addition, SOCS proteins can target the receptor complex and associated signaling proteins for proteasomal degradation through their SOCS boxes, which mediate interactions with elongins B and C to recruit an E3 ubiquitin ligase complex (9,10). Evidence is accumulating which indicates that suppression of SOCS-and SOCS-3 gene expression has been described for various solid tumors and hematologic malignancies (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells

Kuo

Tsai

et al. 2009

Molecular Cancer Therapeutics

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This study investigates the anticancer effect of dehydrocostuslactone (DHE), a plant-derived sesquiterpene lactone, on human breast cancer cells. DHE inhibits cell proliferation by inducing cells to undergo cell cycle arrest and apoptosis. DHE suppresses the expression of cyclin D, cyclin A, cyclin-dependent kinase 2, and cdc25A and increases the amount of p53 and p21, resulting in G 0 /G 1 -S phase arrest in MCF-7 cells. In contrast, DHE caused S-G 2 /M arrest by increasing p21 expression and chk1 activation and inhibiting cyclin A, cyclin B, cdc25A, and cdc25C expression in MDA-MB-231 cells. DHE induces up-regulation of Bax and Bad, down-regulation of Bcl-2 and Bcl-XL, and nuclear relocation of the mitochondrial factors apoptosis-inducing factor and endonuclease G. We also found that DHE inhibits survival signaling through the Janus tyrosine kinase-signal transducer and activator of transcription-3 signaling by increasing the expression of suppressors of cytokine signaling (SOCS)-1 and SOCS-3. Reduction of SOCS-1 and SOCS-3 expression by small interfering RNA inhibits DHE-mediated signal transducer and activator of transcription-3 inhibition, p21 up-regulation, and cyclin-dependent kinase 2 blockade, supporting the hypothesis that DHE inhibits cell cycle progression and cell death through SOCS-1 and SOCS-3. Significantly, animal studies have revealed a 50% reduction in tumor volume after a 45-day treatment period. Taken together, this study provides new insights into the molecular mechanism of the DHE action that may contribute to the chemoprevention of breast cancer.

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“…SOCS proteins have been well recognized as negative regulators of JAK-STAT signaling (1,32). To confirm the physiological effects of socs1a depletion in zebrafish in vivo, the status of the activation of JAK-STAT signaling was analyzed.…”

Section: Resultsmentioning

confidence: 99%

“…The JAK-STAT signaling pathway is one of the core transmission systems that mediates the extracellular signals for the activation of many key signaling cascades involved in various physiological processes. Many cytokines and hormones that are involved in many inflammatory cytokine, growth hormone (GH), and prolactin signaling pathways have been proposed (32). The JAK-STAT pathway can be negatively regulated at multiple levels.…”

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confidence: 99%

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Depletion of suppressor of cytokine signaling-1a causes hepatic steatosis and insulin resistance in zebrafish

Dai

Wang

Jin

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Cytokine receptor signaling through the Jak–Stat–Socs pathway in disease

Cited by 276 publications

References 99 publications

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells

Depletion of suppressor of cytokine signaling-1a causes hepatic steatosis and insulin resistance in zebrafish

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