SOCS3

SOCS3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2BBU, 2HMH, 2JZ3, 4GL9
Identifiers
Aliases	SOCS3 , ATOD4, CIS3, Cish3, SOCS-3, SSI-3, SSI3, suppressor of cytokine signaling 3
External IDs	OMIM: 604176; MGI: 1201791; HomoloGene: 2941; GeneCards: SOCS3; OMA:SOCS3 - orthologs
Gene location (Human) Chr. Chromosome 17 (human) [1] Band 17q25.3 Start 78,356,778 bp [1] End 78,360,077 bp [1]
Gene location (Mouse) Chr. Chromosome 11 (mouse) [2] Band 11|11 E2 Start 117,856,905 bp [2] End 117,860,873 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastric mucosa left uterine tube vena cava gallbladder saphenous vein pericardium seminal vesicula upper lobe of left lung lower lobe of lung lactiferous duct Top expressed in stroma of bone marrow lumbar spinal ganglion granulocyte decidua internal carotid artery mesenteric lymph nodes gastrula islet of Langerhans external carotid artery ciliary body More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein kinase inhibitor activity protein binding phosphotyrosine residue binding 1-phosphatidylinositol-3-kinase regulator activity Cellular component cytosol cytoplasm phosphatidylinositol 3-kinase complex intracellular anatomical structure Biological process regulation of protein phosphorylation trophoblast giant cell differentiation intracellular signal transduction spongiotrophoblast differentiation placenta blood vessel development negative regulation of apoptotic process negative regulation of insulin receptor signaling pathway regulation of interferon-gamma-mediated signaling pathway branching involved in labyrinthine layer morphogenesis protein ubiquitination positive regulation of cell differentiation regulation of cell differentiation regulation of growth negative regulation of signal transduction negative regulation of inflammatory response negative regulation of protein kinase activity negative regulation of receptor signaling pathway via JAK-STAT negative regulation of tyrosine phosphorylation of STAT protein post-translational protein modification cellular response to leukemia inhibitory factor positive regulation of tyrosine phosphorylation of STAT protein receptor signaling pathway via JAK-STAT cytokine-mediated signaling pathway interleukin-6-mediated signaling pathway regulation of phosphatidylinositol 3-kinase activity phosphatidylinositol phosphate biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 9021 12702 Ensembl ENSG00000184557 ENSMUSG00000053113 UniProt O14543 Q6FI39 O35718 RefSeq (mRNA) NM_003955 NM_001378932 NM_001378933 NM_007707 RefSeq (protein) NP_003946 NP_001365861 NP_001365862 NP_003946.3 NP_031733 Location (UCSC) Chr 17: 78.36 – 78.36 Mb Chr 11: 117.86 – 117.86 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Suppressor of cytokine signaling 3 (SOCS3 or SOCS-3) is a protein that in humans is encoded by the SOCS3 gene. ^{[5] [6]} This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling.

SOCS3 is a conserved gene, found in across the animal kingdom, including Drosophila , ^[7] chickens, ^[8] and crocodiles. ^[9]

Function

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. ^[10] But deletion of SOCS3 in the skeletal muscle of mice protects against obesity-related insulin resistance. ^[10]

SOCS3 contributes to both leptin resistance and insulin resistance as a result of increased ceramide synthesis. ^[11] For that reason, studies have shown that removal of the SOCS gene prevents against insulin resistance in obesity ^[10]

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. ^[12]

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

Interactions

SOCS3 has been shown to interact with:

• Erythropoietin receptor, ^{[13] [14]}
• Glycoprotein 130, ^[15]
• Insulin-like growth factor 1 receptor, ^[16]
• Janus kinase 2, ^{[6] [13] [17]}
• PTPN11, ^[15] and
• RAS p21 protein activator 1. ^[18]

Regulation

There is some evidence that the expression of SOCS3 is regulated by the microRNA miR-203, ^{[19] [20]} miR-409-3p and miR-1896. ^[21]

See also

• SOCS
• JAK-STAT signaling pathway

References

1. GRCh38: Ensembl release 89: ENSG00000184557 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000053113 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Minamoto S, Ikegame K, Ueno K, Narazaki M, Naka T, Yamamoto H, Matsumoto T, Saito H, Hosoe S, Kishimoto T (September 1997). "Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3". Biochem Biophys Res Commun. 237 (1): 79–83. doi:10.1006/bbrc.1997.7080. PMID   9266833.
6. Masuhara M, Sakamoto H, Matsumoto A, Suzuki R, Yasukawa H, Mitsui K, Wakioka T, Tanimura S, Sasaki A, Misawa H, Yokouchi M, Ohtsubo M, Yoshimura A (November 1997). "Cloning and characterization of novel CIS family genes". Biochem Biophys Res Commun. 239 (2): 439–46. doi:10.1006/bbrc.1997.7484. PMID   9344848.
7. Stec, Wojciech; Vidal, Oscar; Zeidler, Martin P.; Chernoff, Jonathan (2013). "Drosophila SOCS36E negatively regulates JAK/STAT pathway signaling via two separable mechanisms". Molecular Biology of the Cell. 24 (18): 3000–3009. doi:10.1091/mbc.e13-05-0275. ISSN   1059-1524. PMC   3771960 . PMID   23885117.
8. Nakanoh, Shota; Agata, Kiyokazu (2019). "Evolutionary view of pluripotency seen from early development of non-mammalian amniotes". Developmental Biology. 452 (2): 95–103. doi: 10.1016/j.ydbio.2019.04.014 . ISSN   0012-1606. PMID   31029690.
9. Xia, Tian; Zhang, Lei; Sun, Guolei; Yang, Xiufeng; Zhang, Honghai (2021). "Genomic evidence of adaptive evolution in the reptilian SOCS gene family". PeerJ. 9 e11677. doi: 10.7717/peerj.11677 . ISSN   2167-8359. PMC   8236234 . PMID   34221740.
10. 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 (2013). "Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity". Diabetes . 62 (1): 56–64. doi:10.2337/db12-0443. PMC   3526029 . PMID   22961088.
11. Yang G, Badeanlou L, Bielawski J, Roberts AJ, Hannun YA, Samad F (2009). "Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome". American Journal of Physiology . 297 (1): E211 –E224. doi:10.1152/ajpendo.91014.2008. PMC   2711669 . PMID   19435851.
12. "Entrez Gene: SOCS3 suppressor of cytokine signaling 3".
13. Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I, Yoshimura A (September 2000). "CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2". J. Biol. Chem. 275 (38): 29338–47. doi: 10.1074/jbc.M003456200 . PMID   10882725.
14. Hörtner M, Nielsch U, Mayr LM, Heinrich PC, Haan S (May 2002). "A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor". Eur. J. Biochem. 269 (10): 2516–26. doi: 10.1046/j.1432-1033.2002.02916.x . PMID   12027890.
15. 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 (January 2003). "SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130". J. Biol. Chem. 278 (1): 661–71. doi: 10.1074/jbc.M210552200 . PMID   12403768.
16. Dey BR, Furlanetto RW, Nissley P (November 2000). "Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor". Biochem. Biophys. Res. Commun. 278 (1): 38–43. doi:10.1006/bbrc.2000.3762. PMID   11071852.
17. Sasaki A, Yasukawa H, Suzuki A, Kamizono S, Syoda T, Kinjyo I, Sasaki M, Johnston JA, Yoshimura A (June 1999). "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". Genes Cells. 4 (6): 339–51. doi: 10.1046/j.1365-2443.1999.00263.x . PMID   10421843. S2CID   24871585.
18. Cacalano NA, Sanden D, Johnston JA (May 2001). "Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras". Nat. Cell Biol. 3 (5): 460–5. doi:10.1038/35074525. PMID   11331873. S2CID   19179597.
19. Lena AM, Shalom-Feuerstein R, Rivetti di Val Cervo P, Aberdam D, Knight RA, Melino G, Candi E (2008). "miR-203 represses 'stemness' by repressing DeltaNp63". Cell Death Differ. 15 (7): 1187–95. doi: 10.1038/cdd.2008.69 . PMID   18483491.
20. Wei T, Orfanidis K, Xu N, Janson P, Ståhle M, Pivarcsi A, Sonkoly E (2010). "The expression of microRNA-203 during human skin morphogenesis". Exp Dermatol. 19 (9): 854–6. doi:10.1111/j.1600-0625.2010.01118.x. hdl: 10616/40436 . PMID   20698882. S2CID   30026838.
21. Liu, Xiaomei; Zhou, Feng; Yang, Ying; Wang, Weixiao; Niu, Liping; Zuo, Dongjiao; Li, Xiangyang; Hua, Hui; Zhang, Bo; Kou, Yanbo; Guo, Jingjing (January 2019). "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". Glia. 67 (1): 101–112. doi: 10.1002/glia.23530 . ISSN   1098-1136. PMID   30294880.

Further reading

• Yasukawa H, Sasaki A, Yoshimura A (2000). "Negative regulation of cytokine signaling pathways". Annu. Rev. Immunol. 18: 143–64. doi:10.1146/annurev.immunol.18.1.143. PMID   10837055.
• Kile BT, Schulman BA, Alexander WS, Nicola NA, Martin HM, Hilton DJ (2002). "The SOCS box: a tale of destruction and degradation". Trends Biochem. Sci. 27 (5): 235–41. doi:10.1016/S0968-0004(02)02085-6. PMID   12076535.
• 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 (1999). "The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation". Proc. Natl. Acad. Sci. U.S.A. 96 (5): 2071–6. Bibcode:1999PNAS...96.2071Z. doi: 10.1073/pnas.96.5.2071 . PMC   26738 . PMID   10051596.
• Sasaki A, Yasukawa H, Suzuki A, Kamizono S, Syoda T, Kinjyo I, Sasaki M, Johnston JA, Yoshimura A (1999). "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". Genes Cells. 4 (6): 339–51. doi: 10.1046/j.1365-2443.1999.00263.x . PMID   10421843. S2CID   24871585.
• Marine JC, McKay C, Wang D, Topham DJ, Parganas E, Nakajima H, Pendeville H, Yasukawa H, Sasaki A, Yoshimura A, Ihle JN (1999). "SOCS3 is essential in the regulation of fetal liver erythropoiesis". Cell. 98 (5): 617–27. doi: 10.1016/S0092-8674(00)80049-5 . PMID   10490101. S2CID   15828925.
• Schmitz J, Weissenbach M, Haan S, Heinrich PC, Schaper F (2000). "SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130". J. Biol. Chem. 275 (17): 12848–56. doi: 10.1074/jbc.275.17.12848 . PMID   10777583.
• Ram PA, Waxman DJ (2000). "SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms". J. Biol. Chem. 274 (50): 35553–61. doi: 10.1074/jbc.274.50.35553 . PMID   10585430.
• Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I, Yoshimura A (2000). "CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2". J. Biol. Chem. 275 (38): 29338–47. doi: 10.1074/jbc.M003456200 . PMID   10882725.
• Anhuf D, Weissenbach M, Schmitz J, Sobota R, Hermanns HM, Radtke S, Linnemann S, Behrmann I, Heinrich PC, Schaper F (2000). "Signal transduction of IL-6, leukemia-inhibitory factor, and oncostatin M: structural receptor requirements for signal attenuation". J. Immunol. 165 (5): 2535–43. doi: 10.4049/jimmunol.165.5.2535 . PMID   10946280.
• Bjorbak C, Lavery HJ, Bates SH, Olson RK, Davis SM, Flier JS, Myers MG (2001). "SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985". J. Biol. Chem. 275 (51): 40649–57. doi: 10.1074/jbc.M007577200 . PMID   11018044.
• Shen X, Hong F, Nguyen VA, Gao B (2000). "IL-10 attenuates IFN-alpha-activated STAT1 in the liver: involvement of SOCS2 and SOCS3". FEBS Lett. 480 (2–3): 132–6. doi: 10.1016/S0014-5793(00)01905-0 . PMID   11034314. S2CID   84290049.
• Dey BR, Furlanetto RW, Nissley P (2001). "Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor". Biochem. Biophys. Res. Commun. 278 (1): 38–43. doi:10.1006/bbrc.2000.3762. PMID   11071852.
• Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC   310948 . PMID   11076863.
• Cookson WO, Ubhi B, Lawrence R, Abecasis GR, Walley AJ, Cox HE, Coleman R, Leaves NI, Trembath RC, Moffatt MF, Harper JI (2001). "Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci". Nat. Genet. 27 (4): 372–3. doi:10.1038/86867. PMID   11279517. S2CID   22665448.
• Cacalano NA, Sanden D, Johnston JA (2001). "Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras". Nat. Cell Biol. 3 (5): 460–5. doi:10.1038/35074525. PMID   11331873. S2CID   19179597.
• Roberts AW, Robb L, Rakar S, Hartley L, Cluse L, Nicola NA, Metcalf D, Hilton DJ, Alexander WS (2001). "Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3". Proc. Natl. Acad. Sci. U.S.A. 98 (16): 9324–9. Bibcode:2001PNAS...98.9324R. doi: 10.1073/pnas.161271798 . PMC   55419 . PMID   11481489.
• Dif F, Saunier E, Demeneix B, Kelly PA, Edery M (2001). "Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor". Endocrinology. 142 (12): 5286–93. doi: 10.1210/endo.142.12.8549 . PMID   11713228.
• Bode JG, Ludwig S, Freitas CA, Schaper F, Ruhl M, Melmed S, Heinrich PC, Häussinger D (2002). "The MKK6/p38 mitogen-activated protein kinase pathway is capable of inducing SOCS3 gene expression and inhibits IL-6-induced transcription". Biol. Chem. 382 (10): 1447–53. doi:10.1515/BC.2001.178. PMID   11727828. S2CID   31128727.