Affinage

CISH

Cytokine-inducible SH2-containing protein · UniProt Q9NSE2

Round 2 corrected
Length
258 aa
Mass
28.7 kDa
Annotated
2026-04-28
130 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CISH (cytokine-inducible SH2-containing protein) is a STAT5-induced negative-feedback regulator of JAK–STAT signaling that broadly restrains cytokine responses in hematopoietic and immune cells. Its SH2 domain binds tyrosine-phosphorylated cytokine receptor chains—including IL-2Rβ, EPO-R, GHR, PRLR, and GM-CSFR—to competitively block STAT5 recruitment and activation (PMID:7796808, PMID:10514520, PMID:10585430, PMID:11713228, PMID:32097462). Beyond receptor antagonism, CISH functions as the substrate-recognition subunit of an ElonginB/C–Cullin2 E3 ubiquitin ligase complex that targets the pro-apoptotic protein BimEL and the V-ATPase catalytic subunit ATP6V1A for proteasomal degradation, thereby regulating apoptosis and phagosomal/lysosomal acidification in macrophages and T cells (PMID:18420585, PMID:28954234, PMID:37118554). CISH itself undergoes rapid ubiquitin-dependent proteasomal turnover and is subject to post-transcriptional repression by miR-98, let-7, and miR-944, which together fine-tune the amplitude and duration of its inhibitory activity (PMID:9774439, PMID:19592657, PMID:32961483).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1995 High

    The discovery of CISH as a cytokine-inducible SH2-containing protein that binds phosphorylated IL-3Rβ and EPO-R and suppresses hematopoietic cell growth established it as a new class of negative feedback regulator of cytokine signaling.

    Evidence Co-immunoprecipitation and steroid-inducible expression in IL-3-dependent cell lines with proliferation assays

    PMID:7796808

    Open questions at the time
    • Molecular mechanism of growth suppression unknown
    • Receptor specificity beyond IL-3R and EPO-R uncharacterized
    • Relationship to other SH2-domain inhibitors (SOCS family) undefined
  2. 1998 High

    Demonstration that CISH is ubiquitinated and rapidly degraded by the proteasome—and that blocking proteasomal degradation prolongs EPO-R/STAT5 signaling—revealed a self-limiting regulatory circuit in which CISH's own turnover controls signaling duration.

    Evidence Anti-ubiquitin immunoblotting, proteasome inhibitor treatment (ALLN, lactacystin), phosphorylation kinetics of EPO-R and STAT5

    PMID:9774439

    Open questions at the time
    • E3 ligase responsible for CISH ubiquitination not identified
    • Whether CISH ubiquitination targets receptor complexes for co-degradation not resolved
  3. 1999 High

    Mapping CISH's SH2-dependent binding to IL-2Rβ and to membrane-distal phosphotyrosines on GHR, and showing that this blocks STAT5 activation without inhibiting JAK2 directly, defined a receptor-proximal competitive mechanism distinct from SOCS-1/SOCS-3.

    Evidence Co-IP with IL-2Rβ deletion mutants, SH2-domain dominant-negative mutant, GST-GHR fusion binding assays, STAT5b reporter assays

    PMID:10514520 PMID:10585430

    Open questions at the time
    • Structural basis for selective phosphotyrosine recognition not determined
    • Stoichiometry of CISH at native receptor complexes unknown
  4. 2001 High

    Extension to the prolactin receptor showed CISH inhibits PRL/STAT5 signaling by associating with PRLR, broadening the model to include a role in lactation-related cytokine pathways.

    Evidence Co-IP in HEK293 cells, beta-casein promoter luciferase reporter

    PMID:11713228

    Open questions at the time
    • In vivo relevance for mammary gland biology not tested
    • Binding site on PRLR not mapped
  5. 2003 High

    IL-6/STAT3-driven induction of CISH in liver established a cross-cytokine regulatory axis in which inflammatory IL-6 signaling suppresses GH/STAT5 signaling through CISH upregulation, providing in vivo evidence from IL-6-knockout mice.

    Evidence IL-6 and TNFR1 knockout mice, LPS challenge, immunoblot for STAT5/STAT3 phosphorylation and CIS protein

    PMID:12519742

    Open questions at the time
    • Relative contributions of CISH versus SOCS-3 to GH resistance not separated genetically
    • Tissue-specific regulation beyond liver unexplored
  6. 2008 High

    Identification of CISH as the substrate adaptor of an ElonginB/C–Cullin2 E3 ligase complex that ubiquitinates the pro-apoptotic protein BimEL established a second molecular activity for CISH beyond receptor competition—direct substrate targeting for degradation.

    Evidence Yeast two-hybrid, co-IP, in vitro ubiquitination reconstitution with ElonginB/C-Cullin2-CIS, cancer cell line and specimen correlation

    PMID:18420585

    Open questions at the time
    • Full substrate repertoire of the Cullin2-CISH E3 ligase unknown
    • Structural basis for BimEL recognition not determined
  7. 2009 High

    Discovery that miR-98 and let-7 post-transcriptionally repress CISH by targeting its 3′-UTR, and that CISH in turn promotes IκBα degradation and NF-κB activation, revealed a previously unknown miRNA-regulated layer of CISH control and an unexpected connection to innate immune NF-κB signaling.

    Evidence Luciferase 3′-UTR reporter, miRNA overexpression/knockdown, NF-κB activation assays in cholangiocytes upon LPS and C. parvum infection

    PMID:19592657

    Open questions at the time
    • Mechanism linking CISH to IκBα degradation not elucidated
    • Generalizability of miR-98/let-7 regulation to immune cell types not shown
  8. 2011 Medium

    CISH's role was extended to immune cell differentiation: it terminates STAT5-driven DC progenitor proliferation and promotes type-1 DC maturation required for CTL priming, and it participates in PD-1-dependent Treg expansion during M. tuberculosis infection.

    Evidence CISH knockdown in bone-marrow-derived DCs with flow cytometry and CTL priming assays; PD-1 and CISH siRNA epistasis in M. tuberculosis-stimulated Treg expansion

    PMID:21383382 PMID:22002016

    Open questions at the time
    • Whether CISH is required for DC differentiation in vivo not demonstrated with conditional knockout
    • Mechanism of PD-1-driven CISH induction in Tregs not defined biochemically
  9. 2017 High

    CISH was shown to be exploited by M. tuberculosis: GM-CSF/STAT5-induced CISH targets V-ATPase subunit ATP6V1A for ubiquitin-dependent degradation, impairing phagosomal acidification and enabling intracellular bacterial survival.

    Evidence Macrophage infection, CISH knockdown/inhibition, ubiquitination assay for ATP6V1A, phagosomal acidification and bacterial replication measurements

    PMID:28954234

    Open questions at the time
    • Whether ATP6V1A is a direct Cullin2-CISH E3 substrate or requires additional adaptors not fully resolved
    • Relevance to human TB macrophages in vivo not confirmed
  10. 2020 High

    Genetic deletion of CISH in NK cells revealed that CISH restrains GM-CSF receptor signaling and that its loss exacerbates autoimmune inflammation, establishing CISH as a cell-intrinsic checkpoint on NK cell activation in vivo.

    Evidence CIS-knockout and NK-cell-specific GM-CSFR-deletion mice, arthritis and EAE disease models, cytokine assays

    PMID:32097462

    Open questions at the time
    • Precise signaling intermediates downstream of GM-CSFR that CISH targets in NK cells not identified
    • Therapeutic relevance of CISH modulation in autoimmunity not tested
  11. 2023 High

    Elevated CISH in aged T cells was linked to lysosomal failure via ATP6V1A degradation, causing amphisomal accumulation and extracellular release of mitochondrial DNA—a mechanism contributing to inflammaging—and CISH silencing rescued these defects.

    Evidence CISH overexpression/siRNA in human T cells, lysosomal activity and V-ATPase subunit assays, amphisome/mtDNA imaging, in vivo CISH-deficient CD4+ T cell responses

    PMID:37118554

    Open questions at the time
    • Whether CISH-driven lysosomal dysfunction operates in non-T immune cells during aging is unknown
    • Upstream signals driving age-dependent CISH overexpression not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • A comprehensive structural model of the CISH SH2 domain in complex with phosphorylated receptor peptides and of the Cullin2–ElonginB/C–CISH E3 holoenzyme is lacking, and the full substrate repertoire of the CISH E3 ligase remains undefined.
  • No high-resolution structure of CISH SH2 bound to any receptor phosphopeptide
  • Complete substrate catalog of Cullin2-CISH E3 ligase not established
  • Relative contribution of receptor-blocking versus E3-ligase activity to CISH's physiological effects not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0016874 ligase activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 6 R-HSA-392499 Metabolism of proteins 4
Partners
ATP6V1ABCL2L11CSF2RBEPORGHRIL2RBPRLRRACK1
Complex memberships
ElonginB/C–Cullin2–CISH E3 ubiquitin ligase

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 CIS (cytokine-inducible SH2-containing protein / CISH) was identified as a novel cytokine-inducible immediate-early gene encoding a 257-amino acid SH2-domain-containing protein that stably associates with the tyrosine-phosphorylated beta chain of the IL-3 receptor and the tyrosine-phosphorylated EPO receptor, and forced expression of CIS reduced growth rate of hematopoietic cell lines, demonstrating a negative regulatory role in cytokine signal transduction. Co-immunoprecipitation, steroid-inducible expression system in IL-3-dependent hematopoietic cell lines, proliferation assays The EMBO journal High 7796808
1998 CIS associates with the second tyrosine residue (Tyr401) of the intracellular domain of the erythropoietin receptor. CIS exists in two forms (32 kDa and 37 kDa); the 37-kDa form is ubiquitinated and rapidly degraded by the proteasome. Proteasome inhibitors caused accumulation of ubiquitinated CIS and CIS-EPO receptor complexes, and also prolonged EPO receptor and STAT5 phosphorylation, implicating ubiquitinated CIS in proteasome-mediated inactivation of EPO receptor signaling. Co-immunoprecipitation, anti-ubiquitin immunoblotting, proteasome inhibitor treatment (ALLN, lactacystin), Western blot of receptor/STAT5 phosphorylation The Journal of biological chemistry High 9774439
1999 CIS associates with the IL-2 receptor beta chain (IL-2Rbeta) via the A region (residues 313–382), inhibiting Lck-mediated phosphorylation of IL-2Rbeta and IL-2-mediated STAT5 activation. A dominant-negative CIS mutant with an altered SH2 domain confirmed that the phosphotyrosine-binding capability of the SH2 domain is essential for CIS inhibitory function. Co-immunoprecipitation, in vitro binding assays, transfection with wild-type and SH2 mutant CIS, STAT5 activation assays The Journal of biological chemistry High 10514520
1999 CIS inhibits growth hormone (GH)-stimulated STAT5b activation and STAT5b-dependent transcription by binding to membrane-distal tyrosine residues on the GH receptor (GHR) in a tyrosine-phosphorylation-dependent manner, a mechanism distinct from SOCS-1 (direct JAK2 inhibition) and SOCS-3 (membrane-proximal GHR tyrosines). CIS binding required tyrosine-phosphorylated GHR membrane-distal sequences; SOCS-2 behaved similarly. GST-GHR fusion protein in vitro binding assays, transfection in COS cells, STAT5b reporter assays, JAK2 phosphorylation assays, GHR tyrosine mutants The Journal of biological chemistry High 10585430
2001 CIS suppresses PRL (prolactin) signaling by associating with the PRL receptor (PRLR) and inhibiting STAT5 activation, by a mechanism downstream of and distinct from SOCS-1's inhibition of JAK2. CIS produced ~70% inhibition of PRL-stimulated beta-casein promoter activity; this inhibition required PRLR association. Co-immunoprecipitation, transfection in HEK293 cells, beta-casein promoter luciferase reporter assay, STAT5 activation assay Endocrinology High 11713228
2003 IL-6 inhibits hepatic GH signaling by inducing upregulation of both CIS and SOCS-3 protein through STAT3 activation. In IL-6 knockout mice, LPS-induced suppression of GH-stimulated STAT5 activation was abrogated, and CIS and SOCS-3 were not induced, establishing CIS as part of the IL-6/STAT3-mediated negative feedback on GH/STAT5 signaling in the liver. IL-6 and TNFR1 knockout mouse models, LPS administration, immunoblot for STAT5/STAT3 phosphorylation and CIS/SOCS-3 protein levels, real-time RT-PCR, ELISA American journal of physiology. Gastrointestinal and liver physiology High 12519742
2008 The SOCS box of CIS can function as a modulator of substrate binding, representing a distinct role compared to other SOCS box functions. This places CIS as using the SOCS box not only for E3 ligase recruitment but also for altering its own substrate-binding properties. Structural/biochemical analysis reviewed with experimental data Cytokine & growth factor reviews Low 18948053
2008 RACK1 forms a complex with DLC1 and BimEL (a pro-apoptotic protein), and CIS mediates the degradation of BimEL through an ElonginB/C–Cullin2–CIS ubiquitin-protein isopeptide ligase (E3) complex upon paclitaxel treatment. An inverse correlation between CIS and BimEL levels was observed in ovarian and breast cancer cell lines and specimens. Yeast two-hybrid (identification of RACK1 partners), co-immunoprecipitation, ubiquitination assay with ElonginB/C-Cullin2-CIS complex, Western blot, in vitro and in vivo cancer cell studies The Journal of biological chemistry High 18420585
2009 CIS expression in cholangiocytes is post-transcriptionally regulated by microRNA-98 (miR-98) and let-7, which target the 3'-UTR of CIS mRNA for translational repression without mRNA degradation. LPS stimulation or Cryptosporidium parvum infection decreased miR-98 and let-7 levels, relieving CIS translational repression and increasing CIS protein. CIS in turn enhanced IκBα degradation and regulated NF-κB activation in cholangiocytes. Luciferase reporter assay with CIS 3'-UTR, miRNA overexpression/knockdown, CIS siRNA and overexpression, NF-κB activation assays, Western blot Journal of immunology High 19592657
2010 CISH polymorphisms in the promoter region are associated with susceptibility to bacteremia, tuberculosis, and severe malaria. The -292 variant reduced CISH expression by 25–40% in peripheral blood mononuclear cells stimulated to produce IL-2, demonstrating that CISH controls interleukin-2 signaling and that its expression level determines host resistance to infectious diseases. Case-control association study, functional PBMC stimulation assays measuring CISH mRNA levels by genotype The New England journal of medicine Medium 20484391
2011 CISH is induced during dendritic cell (DC) development from bone marrow cells and plays a role in type 1 DC development and DC-mediated CTL activation. CISH knockdown increased DC yield (via cell-cycle activation and reduced apoptosis) but reduced MHC class I, co-stimulatory molecule expression, pro-inflammatory cytokines, and impaired CTL priming. CISH-mediated negative feedback on STAT5 activation terminates DC progenitor proliferation and promotes DC differentiation into CTL stimulators. CISH knockdown in bone marrow-derived DCs, flow cytometry, cell cycle analysis, STAT5 phosphorylation assay, T cell proliferation assay, tumor immunotherapy model European journal of immunology Medium 22002016
2011 CISH (CIS) associates with the IL-2 receptor complex and regulates Treg expansion induced by Mycobacterium tuberculosis. PD-1 siRNA inhibited CISH expression in expanded Tregs, placing CIS downstream of PD-1 in the M. tuberculosis-induced Treg expansion pathway. CISH siRNA and anti-PD-1 siRNA each blocked M. tuberculosis-stimulated Treg expansion from CD4+CCR4+ cells. siRNA knockdown of PD-1 and CISH, flow cytometry for Treg expansion, cytokine measurement (TGF-β, IL-10, IFN-γ) The Journal of infectious diseases Medium 21383382
2017 M. tuberculosis infection of macrophages induces GM-CSF secretion, which triggers STAT5-mediated expression of CISH; CISH then selectively targets the V-ATPase catalytic subunit A (ATP6V1A) for ubiquitination and proteasomal degradation, impairing phagosomal acidification and promoting mycobacterial survival. Inhibition of CISH expression reduced M. tuberculosis replication in macrophages. Macrophage infection models, CISH knockdown/inhibition, ubiquitination assay, V-ATPase subunit localization and abundance assays, bacterial replication assays Cell reports High 28954234
2020 CIS (CISH) negatively regulates GM-CSF receptor signaling in NK cells. CIS-deficient NK cells displayed enhanced GM-CSF-driven signaling, and CISH deletion in NK cells exacerbated autoantibody-mediated inflammatory arthritis and experimental allergic encephalomyelitis, demonstrating that endogenous CIS provides a key brake on GM-CSF receptor-mediated NK cell activation. CIS knockout mouse models, GM-CSF fate reporter mice, cytokine production assays, NK cell-specific GM-CSF deletion, disease models (arthritis, EAE) The Journal of experimental medicine High 32097462
2023 CISH expression is elevated in T cells from older adults and impairs lysosomal function by targeting ATP6V1A (V-ATPase proton pump catalytic subunit) for proteasomal degradation. Impaired lysosomal activity leads to accumulation of multivesicular bodies and amphisomes and export of mitochondrial DNA (mtDNA) into the environment, contributing to inflammaging. CISH silencing in T cells from older adults restored lysosomal activity and prevented amphisomal mtDNA release. CISH overexpression and siRNA knockdown in T cells, lysosomal activity assays, V-ATPase subunit abundance measurement, multivesicular body/amphisome imaging, mtDNA release assay, in vivo antigen-specific response in CISH-deficient CD4+ T cells Nature aging High 37118554
2020 miR-944 directly targets CISH mRNA, downregulating CISH protein in oral squamous cell carcinoma (OSCC). Loss of CISH leads to increased STAT3 phosphorylation, pro-inflammatory cytokine secretion, and enhanced cell migration and invasion; restoration of CISH abolished these oncogenic effects of miR-944, placing CISH as a direct post-transcriptional target of miR-944 that modulates STAT3 activity. Luciferase reporter assay (3'-UTR targeting), qRT-PCR, immunohistochemistry, gain- and loss-of-function (miR-944 and CISH), transwell migration/invasion assay, ELISA for cytokines Neoplasia High 32961483
2014 CISH promoter polymorphisms (rs414171 and rs809451) alter CISH transcriptional activity; the G(-809451)-A(-414171)-C(-622502) haplotype drove 5.43-fold higher reporter expression compared to the risk haplotype. PBMCs carrying rs414171TT showed reduced CISH mRNA and increased IL-12p40 and IL-10 production, demonstrating that CISH promoter variants functionally regulate CISH expression and downstream cytokine responses in the context of TB susceptibility. Luciferase reporter assay (promoter variants), qRT-PCR of CISH mRNA in PBMCs, ELISA for IL-12p40 and IL-10, case-control genotyping PloS one Medium 24632804

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2007 SOCS proteins, cytokine signalling and immune regulation. Nature reviews. Immunology 1305 17525754
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1995 A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. The EMBO journal 630 7796808
2005 A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 568 16273093
2004 The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annual review of immunology 556 15032587
2008 SOCS regulation of the JAK/STAT signalling pathway. Seminars in cell & developmental biology 497 18708154
1999 The role of SOCS-3 in leptin signaling and leptin resistance. The Journal of biological chemistry 494 10514492
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2019 Mechanistic Insights into the cis- and trans-Acting DNase Activities of Cas12a. Molecular cell 417 30639240
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2002 The SOCS box: a tale of destruction and degradation. Trends in biochemical sciences 359 12076535
1999 SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. The Journal of biological chemistry 287 10585430
2001 The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2. The Journal of biological chemistry 264 11278610
2000 CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. The Journal of biological chemistry 259 10882725
2007 Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Molecular immunology 255 17208301
2004 Functional proteomics mapping of a human signaling pathway. Genome research 247 15231748
2002 Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. The Journal of clinical investigation 247 12438448
1999 Autoregulation of pituitary corticotroph SOCS-3 expression: characterization of the murine SOCS-3 promoter. Proceedings of the National Academy of Sciences of the United States of America 243 10359822
2013 Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein. Proceedings of the National Academy of Sciences of the United States of America 235 23898208
2009 Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function. Trends in immunology 234 19879803
2005 Activation of SOCS-3 by resistin. Molecular and cellular biology 209 15684405
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2002 Suppressors of cytokine signalling: SOCS. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 174 12645661
2013 SOCS proteins in development and disease. American journal of clinical and experimental immunology 172 23885323
2002 Pim serine/threonine kinases regulate the stability of Socs-1 protein. Proceedings of the National Academy of Sciences of the United States of America 167 11854514
2006 Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions. Cytokine & growth factor reviews 166 17070092
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2013 Suppression of cytokine signaling: the SOCS perspective. Cytokine & growth factor reviews 155 23545160
2008 The many faces of the SOCS box. Cytokine & growth factor reviews 155 18948053
2006 trans meets cis in MADS science. Trends in plant science 155 16616581
1998 Proteasomes regulate erythropoietin receptor and signal transducer and activator of transcription 5 (STAT5) activation. Possible involvement of the ubiquitinated Cis protein. The Journal of biological chemistry 154 9774439
2001 The suppressors of cytokine signalling (SOCS). Cellular and molecular life sciences : CMLS 141 11706989
2021 SOCS Proteins in Immunity, Inflammatory Diseases, and Immune-Related Cancer. Frontiers in medicine 137 34604264
2005 Negative regulation of cytokine signaling and immune responses by SOCS proteins. Arthritis research & therapy 135 15899058
2017 Cis- and trans-acting lncRNAs in pluripotency and reprogramming. Current opinion in genetics & development 134 28843809
2014 The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions in human cells. Nature methods 131 24658140
2000 cis- and trans-acting elements in flavivirus RNA replication. Journal of virology 130 10708442
2002 Suppressors of cytokine signaling (SOCS): inhibitors of the JAK/STAT pathway. Shock (Augusta, Ga.) 126 11837794
2002 Determination of HER2 gene amplification by chromogenic in situ hybridization (CISH) in archival breast carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 114 12065780
2014 In silico prediction of physical protein interactions and characterization of interactome orphans. Nature methods 112 25402006
2002 Impaired IFN-gamma-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1. Journal of immunology (Baltimore, Md. : 1950) 110 12077274
2004 Regulation of the immune system by SOCS family adaptor proteins. Seminars in immunology 108 15541651
2002 The tumor suppressor activity of SOCS-1. Oncogene 108 12080466
2010 Viral exploitation of host SOCS protein functions. Journal of virology 106 21084484
2010 CISH and susceptibility to infectious diseases. The New England journal of medicine 103 20484391
2009 MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge. Journal of immunology (Baltimore, Md. : 1950) 100 19592657
1999 Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction. Journal of leukocyte biology 98 10534114
1979 Binding of cis- and trans-dichlorodiammineplatinum(II) to the nucleosome core. Proceedings of the National Academy of Sciences of the United States of America 98 293706
2012 The SOCS box-adapting proteins for ubiquitination and proteasomal degradation. IUBMB life 97 22362562
2002 TRIM8/GERP RING finger protein interacts with SOCS-1. The Journal of biological chemistry 97 12163497
2003 Negative regulation of FAK signaling by SOCS proteins. The EMBO journal 92 14517242
2017 Suppressors of cytokine signaling: Potential immune checkpoint molecules for cancer immunotherapy. Cancer science 90 28188673
2009 TRPC channels as STIM1-regulated SOCs. Channels (Austin, Tex.) 90 19574740
2007 Reciprocal regulation of SOCS 1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme. Clinical cancer research : an official journal of the American Association for Cancer Research 86 17438093
1999 CIS associates with the interleukin-2 receptor beta chain and inhibits interleukin-2-dependent signaling. The Journal of biological chemistry 86 10514520
2014 SOCS proteins in regulation of receptor tyrosine kinase signaling. Cellular and molecular life sciences : CMLS 85 24705897
2004 Calcium entry mediated by SOCs and TRP channels: variations and enigma. Biochimica et biophysica acta 83 15590052
2020 NK cell-derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS. The Journal of experimental medicine 82 32097462
2014 Suppressor of cytokine signalling (SOCS) proteins as guardians of inflammatory responses critical for regulating insulin sensitivity. The Biochemical journal 82 24966052
2020 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell reports 79 32814053
2009 Regulation of cytokine signaling by the SOCS and Spred family proteins. The Keio journal of medicine 79 19597303
2003 Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3. American journal of physiology. Gastrointestinal and liver physiology 78 12519742
2007 The expression of SOCS is altered in rheumatoid arthritis. Rheumatology (Oxford, England) 76 17726036
2002 Cis- and trans-activation of hormone receptors: the LH receptor. Molecular endocrinology (Baltimore, Md.) 76 12040016
2004 Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling. The Journal of biological chemistry 72 14707129
2015 Kinase inhibition, competitive binding and proteasomal degradation: resolving the molecular function of the suppressor of cytokine signaling (SOCS) proteins. Immunological reviews 69 26085211
2017 Mycobacterium tuberculosis Controls Phagosomal Acidification by Targeting CISH-Mediated Signaling. Cell reports 63 28954234
2000 Expression of "suppressor of cytokine signalling" (SOCS) genes in the developing and adult mouse nervous system. The Journal of comparative neurology 62 10867663
1999 Aberrant hematopoiesis in mice with inactivation of the gene encoding SOCS-1. Leukemia 62 10360382
2020 Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D. Nature communications 60 31980649
2011 Suppressors of cytokine signalling (SOCS) are reduced in osteoarthritis. Biochemical and biophysical research communications 60 21352802
2000 The suppressors of cytokine signaling (SOCS) proteins: important feedback inhibitors of cytokine action. Experimental hematology 60 11027828
2013 Regulation of Janus kinases by SOCS proteins. Biochemical Society transactions 58 23863176
2011 Programmed death 1 and cytokine inducible SH2-containing protein dependent expansion of regulatory T cells upon stimulation With Mycobacterium tuberculosis. The Journal of infectious diseases 58 21383382
2000 Regulation of SOCS-1 expression by translational repression. The Journal of biological chemistry 58 10764816
2019 ARIH2 Is a Vif-Dependent Regulator of CUL5-Mediated APOBEC3G Degradation in HIV Infection. Cell host & microbe 57 31253590
2008 The role of SOCS-3 protein in leptin resistance and obesity. Acta medica Indonesiana 56 18560028
2008 RACK1 and CIS mediate the degradation of BimEL in cancer cells. The Journal of biological chemistry 55 18420585
2004 Analysis of SOCS-3 promoter responses to interferon gamma. The Journal of biological chemistry 55 14742442
2022 Role of lncRNAs in cis- and trans-regulatory responses to salt in Populus trichocarpa. The Plant journal : for cell and molecular biology 54 35218100
2017 Understanding the role of SOCS signaling in neurodegenerative diseases: Current and emerging concepts. Cytokine & growth factor reviews 54 28801024
2003 Are SOCS suppressors, regulators, and degraders? Journal of leukocyte biology 52 14694187
2001 Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor. Endocrinology 52 11713228
2002 Cytokine signaling in the brain: putting a SOCS in it? Journal of neuroscience research 51 11835308
2022 Identification of autosomal cis expression quantitative trait methylation (cis eQTMs) in children's blood. eLife 50 35302492
2004 Evaluation of epidermal growth factor receptor (EGFR) by chromogenic in situ hybridization (CISH) and immunohistochemistry (IHC) in archival gliomas using bright-field microscopy. Diagnostic molecular pathology : the American journal of surgical pathology, part B 50 15163002
2011 Trans-, cis-, and dihydro-resveratrol: a comparative study. Chemistry Central journal 49 22185600
2005 Regulation of pancreatic beta-cell mass and proliferation by SOCS-3. Journal of molecular endocrinology 46 16216905
2023 CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging. Nature aging 45 37118554
2004 Regulation of TLR signaling and inflammation by SOCS family proteins. Journal of leukocyte biology 45 14726494
2005 Hypermethylation of the suppressor of cytokine signalling-1 (SOCS-1) in myelodysplastic syndrome. British journal of haematology 44 16029449
2011 CISH is induced during DC development and regulates DC-mediated CTL activation. European journal of immunology 43 22002016
2020 SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19. Frontiers in immunology 39 33193390
2018 Understanding SOCS protein specificity. Growth factors (Chur, Switzerland) 38 30318950
2005 Suppressor of cytokine signalling 2 (SOCS-2) expression in breast carcinoma. Journal of clinical pathology 38 16189149
2018 Suppressor of cytokine signaling (SOCS) genes are downregulated in breast cancer. World journal of surgical oncology 37 30453988
2006 SOCS proteins and caveolin-1 as negative regulators of endocrine signaling. Trends in endocrinology and metabolism: TEM 37 16616514
2020 MiR-944/CISH mediated inflammation via STAT3 is involved in oral cancer malignance by cigarette smoking. Neoplasia (New York, N.Y.) 36 32961483
2015 Gene delivery of suppressors of cytokine signaling (SOCS) inhibits inflammation and atherosclerosis development in mice. Basic research in cardiology 36 25604439
2020 Extensive Shifts from Cis- to Trans-splicing of Gymnosperm Mitochondrial Introns. Molecular biology and evolution 34 32027368
2007 Knocking off SOCS genes in the mammary gland. Cell cycle (Georgetown, Tex.) 33 17377501
2003 Negative regulation of cytokine signaling by CIS/SOCS family proteins and their roles in inflammatory diseases. Reviews of physiology, biochemistry and pharmacology 33 12687406
2009 Knocking off the suppressors of cytokine signaling (SOCS): their roles in mammalian pregnancy. Journal of reproductive immunology 31 19853926
2009 SOCS-6 negatively regulates T cell activation through targeting p56lck to proteasomal degradation. The Journal of biological chemistry 30 20007709
2001 Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy. American journal of physiology. Regulatory, integrative and comparative physiology 30 11705792
2015 Cis- and trans-regulation in X inactivation. Chromosoma 29 26198462
2010 Flexible recognition of the tRNA G18 methylation target site by TrmH methyltransferase through first binding and induced fit processes. The Journal of biological chemistry 29 20053984
1988 Hemoglobin hafnia: alpha 2 (beta 116 (G18) His----Gln)2; a new hemoglobin variant mistaken for glycated hemoglobin. Biochimica et biophysica acta 29 3395624
2021 The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia. Cancers 28 34439155
2019 Upregulation of Complement Factor H by SOCS-1/3⁻STAT4 in Lung Cancer. Cancers 27 30987235
2013 Conserved inhibitory role of teleost SOCS-1s in IFN signaling pathways. Developmental and comparative immunology 27 24183820
2003 Differential regulation of SOCS genes in normal and transformed erythroid cells. Oncogene 27 12761492
2018 SOCS-mediated immunomodulation of natural killer cells. Cytokine 25 29609875
2014 Suppressors of cytokine signaling (SOCS) and type 2 diabetes. Molecular biology reports 24 24414000
1975 Hemoglobin-A2-Coburg or alpha2delta2116Arg leads to His (G18). Biochimica et biophysica acta 24 1148221
2007 Synthesis, characterization and antiproliferative studies of the enantiomers of cis-[(1,2-camphordiamine)dichloro]platinum(II) complexes. Bioorganic & medicinal chemistry 23 18036822
2013 Multiple roles of SOCS proteins: differential expression of SOCS1 and SOCS3 in atherosclerosis. International journal of molecular medicine 22 23545584
2014 Genetic contribution of CISH promoter polymorphisms to susceptibility to tuberculosis in Chinese children. PloS one 21 24632804
2013 SOCS and diabetes--ups and downs of a turbulent relationship. Cell biochemistry and function 21 23335325
2021 SOCS proteins and their roles in the development of glioblastoma. Oncology letters 20 34820004
2021 Localization of RNAs in the nucleus: cis- and trans- regulation. RNA biology 19 33682620
2019 The Pros1/Tyro3 axis protects against periodontitis by modulating STAT/SOCS signalling. Journal of cellular and molecular medicine 19 30729671
2016 Identification and expression analysis of suppressors of cytokine signaling (SOCS) of Japanese flounder Paralichthys olivaceus. Fish & shellfish immunology 19 27640157
2006 Abundant hypermethylation of SOCS-1 in clinically silent pituitary adenomas. Acta neuropathologica 19 16421738
2021 SOCS, SPRED, and NR4a: Negative regulators of cytokine signaling and transcription in immune tolerance. Proceedings of the Japan Academy. Series B, Physical and biological sciences 17 34121041
2018 Cleavage of poly(cis-1,4-isoprene) rubber as solid substrate by cultures of Gordonia polyisoprenivorans. New biotechnology 17 29530668