SOCS3

The expression of SOCS3 gene is induced by various cytokines, including IL6, IL10, and interferon (IFN)-gamma.

For signaling of IL-6, Epo, GCSF and Leptin, binding of SOCS3 to the respective cytokine receptor has been found to be crucial for the inhibitory function of SOCS3.

Overexpression of SOCS3 inhibits insulin signaling in adipose tissue and the liver, but not in muscle.{{cite journal | vauthors=Jorgensen SB, O'Neill HM, Sylow L, Honeyman J, Hewitt KA, Palanivel R, Fullerton MD, Öberg L, Balendran A, Galic S, van der Poel C, Trounce IA, Lynch GS, Schertzer JD, Steinberg GR | title=Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity | journal= Diabetes | volume=62 | issue=1 | pages=56–64| year=2013 | url=http://diabetes.diabetesjournals.org/content/62/1/56.long | doi= 10.2337/db12-0443 | pmc=3526029 | pmid = 22961088 }} But deletion of SOCS3 in the skeletal muscle of mice protects against obesity-related insulin resistance.

SOCS3 contributes to both leptin resistance and insulin resistance as a result of increased ceramide synthesis.{{cite journal | vauthors = Yang G, Badeanlou L, Bielawski J, Roberts AJ, Hannun YA, Samad F | title = Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome | journal = American Journal of Physiology | volume = 297 | issue = 1 | pages = E211–E224 | year = 2009 | pmid = 19435851 | pmc = 2711669 | doi = 10.1152/ajpendo.91014.2008 }} For that reason, studies have shown that removal of the SOCS gene prevents against insulin resistance in obesity

Studies of the mouse counterpart of this gene suggested the roles of this gene in the negative regulation of fetal liver hematopoiesis, and placental development.{{cite web | title = Entrez Gene: SOCS3 suppressor of cytokine signaling 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9021}}

The SOCS3 protein can bind to JAK2 kinase, and inhibits the activity of JAK2 kinase.

SOCS3 has been shown to interact with:

• Erythropoietin receptor,{{cite journal | vauthors = Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I, Yoshimura A | title = CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2 | journal = J. Biol. Chem. | volume = 275 | issue = 38 | pages = 29338–47 | date = September 2000 | pmid = 10882725 | doi = 10.1074/jbc.M003456200 | doi-access = free }}{{cite journal | vauthors = Hörtner M, Nielsch U, Mayr LM, Heinrich PC, Haan S | title = A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor | journal = Eur. J. Biochem. | volume = 269 | issue = 10 | pages = 2516–26 | date = May 2002 | pmid = 12027890 | doi = 10.1046/j.1432-1033.2002.02916.x| doi-access = free }}
• Glycoprotein 130,
• Insulin-like growth factor 1 receptor,{{cite journal | vauthors = Dey BR, Furlanetto RW, Nissley P | title = Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor | journal = Biochem. Biophys. Res. Commun. | volume = 278 | issue = 1 | pages = 38–43 | date = November 2000 | pmid = 11071852 | doi = 10.1006/bbrc.2000.3762 | url = https://zenodo.org/record/1229526 }}
• Janus kinase 2,{{cite journal | vauthors = Sasaki A, Yasukawa H, Suzuki A, Kamizono S, Syoda T, Kinjyo I, Sasaki M, Johnston JA, Yoshimura A | title = Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain | journal = Genes Cells | volume = 4 | issue = 6 | pages = 339–51 | date = June 1999 | pmid = 10421843 | doi = 10.1046/j.1365-2443.1999.00263.x| s2cid = 24871585 | doi-access = free }}
• PTPN11,{{cite journal | vauthors = Lehmann U, Schmitz J, Weissenbach M, Sobota RM, Hortner M, Friederichs K, Behrmann I, Tsiaris W, Sasaki A, Schneider-Mergener J, Yoshimura A, Neel BG, Heinrich PC, Schaper F | title = SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130 | journal = J. Biol. Chem. | volume = 278 | issue = 1 | pages = 661–71 | date = January 2003 | pmid = 12403768 | doi = 10.1074/jbc.M210552200 | doi-access = free }} and
• RAS p21 protein activator 1.{{cite journal | vauthors = Cacalano NA, Sanden D, Johnston JA | title = Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras | journal = Nat. Cell Biol. | volume = 3 | issue = 5 | pages = 460–5 | date = May 2001 | pmid = 11331873 | doi = 10.1038/35074525 | s2cid = 19179597 }}

There is some evidence that the expression of SOCS3 is regulated by the microRNA miR-203,{{cite journal | vauthors = Lena AM, Shalom-Feuerstein R, Rivetti di Val Cervo P, Aberdam D, Knight RA, Melino G, Candi E | title = miR-203 represses 'stemness' by repressing DeltaNp63. | journal = Cell Death Differ | volume = 15 | issue = 7 | pages = 1187–95 | year = 2008 | pmid = 18483491 | doi = 10.1038/cdd.2008.69 | doi-access = free }}{{cite journal | vauthors = Wei T, Orfanidis K, Xu N, Janson P, Ståhle M, Pivarcsi A, Sonkoly E | title = The expression of microRNA-203 during human skin morphogenesis. | journal = Exp Dermatol | volume = 19 | issue = 9 | pages = 854–6 | year = 2010 | pmid = 20698882 | doi = 10.1111/j.1600-0625.2010.01118.x | hdl = 10616/40436 | s2cid = 30026838 | hdl-access = free }} miR-409-3p and miR-1896.{{Cite journal|last1=Liu|first1=Xiaomei|last2=Zhou|first2=Feng|last3=Yang|first3=Ying|last4=Wang|first4=Weixiao|last5=Niu|first5=Liping|last6=Zuo|first6=Dongjiao|last7=Li|first7=Xiangyang|last8=Hua|first8=Hui|last9=Zhang|first9=Bo|last10=Kou|first10=Yanbo|last11=Guo|first11=Jingjing|date=January 2019|title=MiR-409-3p and MiR-1896 co-operatively participate in IL-17-induced inflammatory cytokine production in astrocytes and pathogenesis of EAE mice via targeting SOCS3/STAT3 signaling|journal=Glia|volume=67|issue=1|pages=101–112|doi=10.1002/glia.23530|issn=1098-1136|pmid=30294880|doi-access=free}}

• SOCS
• JAK-STAT signaling pathway

{{reflist|30em}}

{{refbegin|35em}}

• {{cite journal | vauthors = Yasukawa H, Sasaki A, Yoshimura A | title = Negative regulation of cytokine signaling pathways. | journal = Annu. Rev. Immunol. | volume = 18 | pages = 143–64 | year = 2000 | pmid = 10837055 | doi = 10.1146/annurev.immunol.18.1.143 }}
• {{cite journal | vauthors = Kile BT, Schulman BA, Alexander WS, Nicola NA, Martin HM, Hilton DJ | title = The SOCS box: a tale of destruction and degradation. | journal = Trends Biochem. Sci. | volume = 27 | issue = 5 | pages = 235–41 | year = 2002 | pmid = 12076535 | doi = 10.1016/S0968-0004(02)02085-6 }}
• {{cite journal | vauthors = Zhang JG, Farley A, Nicholson SE, Willson TA, Zugaro LM, Simpson RJ, Moritz RL, Cary D, Richardson R, Hausmann G, Kile BJ, Kent SB, Alexander WS, Metcalf D, Hilton DJ, Nicola NA, Baca M | title = The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 5 | pages = 2071–6 | year = 1999 | pmid = 10051596 | pmc = 26738 | doi = 10.1073/pnas.96.5.2071 | bibcode = 1999PNAS...96.2071Z | doi-access = free }}
• {{cite journal | vauthors = Sasaki A, Yasukawa H, Suzuki A, Kamizono S, Syoda T, Kinjyo I, Sasaki M, Johnston JA, Yoshimura A | title = Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain. | journal = Genes Cells | volume = 4 | issue = 6 | pages = 339–51 | year = 1999 | pmid = 10421843 | doi = 10.1046/j.1365-2443.1999.00263.x | s2cid = 24871585 | doi-access = free }}
• {{cite journal | vauthors = Marine JC, McKay C, Wang D, Topham DJ, Parganas E, Nakajima H, Pendeville H, Yasukawa H, Sasaki A, Yoshimura A, Ihle JN | title = SOCS3 is essential in the regulation of fetal liver erythropoiesis. | journal = Cell | volume = 98 | issue = 5 | pages = 617–27 | year = 1999 | pmid = 10490101 | doi = 10.1016/S0092-8674(00)80049-5 | s2cid = 15828925 | doi-access = free }}
• {{cite journal | vauthors = Schmitz J, Weissenbach M, Haan S, Heinrich PC, Schaper F | title = SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130. | journal = J. Biol. Chem. | volume = 275 | issue = 17 | pages = 12848–56 | year = 2000 | pmid = 10777583 | doi = 10.1074/jbc.275.17.12848 | doi-access = free }}
• {{cite journal | vauthors = Ram PA, Waxman DJ | title = SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. | journal = J. Biol. Chem. | volume = 274 | issue = 50 | pages = 35553–61 | year = 2000 | pmid = 10585430 | doi = 10.1074/jbc.274.50.35553 | doi-access = free }}
• {{cite journal | vauthors = Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I, Yoshimura A | title = CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. | journal = J. Biol. Chem. | volume = 275 | issue = 38 | pages = 29338–47 | year = 2000 | pmid = 10882725 | doi = 10.1074/jbc.M003456200 | doi-access = free }}
• {{cite journal | vauthors = Anhuf D, Weissenbach M, Schmitz J, Sobota R, Hermanns HM, Radtke S, Linnemann S, Behrmann I, Heinrich PC, Schaper F | title = Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: structural receptor requirements for signal attenuation. | journal = J. Immunol. | volume = 165 | issue = 5 | pages = 2535–43 | year = 2000 | pmid = 10946280 | doi = 10.4049/jimmunol.165.5.2535 | doi-access = free }}
• {{cite journal | vauthors = Bjorbak C, Lavery HJ, Bates SH, Olson RK, Davis SM, Flier JS, Myers MG | title = SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. | journal = J. Biol. Chem. | volume = 275 | issue = 51 | pages = 40649–57 | year = 2001 | pmid = 11018044 | doi = 10.1074/jbc.M007577200 | doi-access = free }}
• {{cite journal | vauthors = Shen X, Hong F, Nguyen VA, Gao B | title = IL-10 attenuates IFN-alpha-activated STAT1 in the liver: involvement of SOCS2 and SOCS3. | journal = FEBS Lett. | volume = 480 | issue = 2–3 | pages = 132–6 | year = 2000 | pmid = 11034314 | doi = 10.1016/S0014-5793(00)01905-0 | s2cid = 84290049 | doi-access = free }}
• {{cite journal | vauthors = Dey BR, Furlanetto RW, Nissley P | title = Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor | journal = Biochem. Biophys. Res. Commun. | volume = 278 | issue = 1 | pages = 38–43 | year = 2001 | pmid = 11071852 | doi = 10.1006/bbrc.2000.3762 | url = https://zenodo.org/record/1229526 }}
• {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Res. | volume = 10 | issue = 11 | pages = 1788–95 | year = 2001 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }}
• {{cite journal | vauthors = Cookson WO, Ubhi B, Lawrence R, Abecasis GR, Walley AJ, Cox HE, Coleman R, Leaves NI, Trembath RC, Moffatt MF, Harper JI | title = Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci | journal = Nat. Genet. | volume = 27 | issue = 4 | pages = 372–3 | year = 2001 | pmid = 11279517 | doi = 10.1038/86867 | s2cid = 22665448 }}
• {{cite journal | vauthors = Cacalano NA, Sanden D, Johnston JA | title = Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras | journal = Nat. Cell Biol. | volume = 3 | issue = 5 | pages = 460–5 | year = 2001 | pmid = 11331873 | doi = 10.1038/35074525 | s2cid = 19179597 }}
• {{cite journal | vauthors = Roberts AW, Robb L, Rakar S, Hartley L, Cluse L, Nicola NA, Metcalf D, Hilton DJ, Alexander WS | title = Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 16 | pages = 9324–9 | year = 2001 | pmid = 11481489 | pmc = 55419 | doi = 10.1073/pnas.161271798 | bibcode = 2001PNAS...98.9324R | doi-access = free }}
• {{cite journal | vauthors = Dif F, Saunier E, Demeneix B, Kelly PA, Edery M | title = Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor | journal = Endocrinology | volume = 142 | issue = 12 | pages = 5286–93 | year = 2001 | pmid = 11713228 | doi = 10.1210/endo.142.12.8549 | doi-access = free }}
• {{cite journal | vauthors = Bode JG, Ludwig S, Freitas CA, Schaper F, Ruhl M, Melmed S, Heinrich PC, Häussinger D | title = The MKK6/p38 mitogen-activated protein kinase pathway is capable of inducing SOCS3 gene expression and inhibits IL-6-induced transcription | journal = Biol. Chem. | volume = 382 | issue = 10 | pages = 1447–53 | year = 2002 | pmid = 11727828 | doi = 10.1515/BC.2001.178 | s2cid = 31128727 }}

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{{JAK-STAT signaling pathway}}