SOCS3 explained

Suppressor of cytokine signaling 3 (SOCS3 or SOCS-3) is a protein that in humans is encoded by the SOCS3 gene.^{[1] [2]} 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,^[3] chickens,^[4] and crocodiles.^[5]

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.^[6] But deletion of SOCS3 in the skeletal muscle of mice protects against obesity-related insulin resistance.^[6]

SOCS3 contributes to both leptin resistance and insulin resistance as a result of increased ceramide synthesis.^[7] For that reason, studies have shown that removal of the SOCS gene prevents against insulin resistance in obesity^[6]

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.^[8]

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,^{[9] [10]}
• Glycoprotein 130,
• Insulin-like growth factor 1 receptor,^[11]
• Janus kinase 2,^{[9] [12]}
• PTPN11,^[13] and
• RAS p21 protein activator 1.^[14]

Regulation

There is some evidence that the expression of SOCS3 is regulated by the microRNA miR-203,^{[15] [16]} miR-409-3p and miR-1896.^[17]

See also

• SOCS
• JAK-STAT signaling pathway

Further reading

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

Notes and References

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