# SOCS3

## Overview
The SOCS3 gene encodes the suppressor of cytokine signaling 3 protein, a pivotal component in the regulation of cytokine signaling pathways, particularly the JAK/STAT pathway. As a member of the SOCS family, SOCS3 functions primarily as a negative feedback regulator, modulating immune responses and maintaining cellular homeostasis. The protein is characterized by a central SH2 domain, a SOCS box domain, and a kinase inhibitory region (KIR), which collectively facilitate its role in inhibiting Janus kinases (JAKs) and promoting the degradation of signaling proteins through ubiquitin ligase complexes. SOCS3's regulatory functions are crucial in various physiological processes, including T cell differentiation and immune response modulation, and its dysregulation is implicated in numerous pathological conditions such as cancer, autoimmune disorders, and inflammatory diseases (Mahony2016SOCS3; Babon2006The; Dai2022SOCS3).

## Structure
The SOCS3 protein is characterized by a central SH2 domain, which is crucial for its interaction with phosphorylated tyrosine residues on target proteins. This domain is extended by regions known as N-ESS and C-ESS, which enhance its binding affinity to phosphorylated tyrosines (Babon2006The). The SH2 domain includes a 35-residue unstructured PEST motif that regulates the protein's stability by increasing its turnover, although this motif is not essential for inhibiting STAT proteins (Babon2006The).

SOCS3 also contains a SOCS box domain at the C-terminus, which is involved in the recruitment of ubiquitin ligase complexes, facilitating the degradation of signaling proteins. This domain interacts with elonginBC and cullin5, forming a stable ternary complex (Babon2008The). The SOCS box is disordered in isolation but becomes structured upon binding with elonginBC (Babon2008The).

The protein's kinase inhibitory region (KIR) is essential for inhibiting JAK kinases by blocking substrate binding. This region is unstructured in isolation but folds upon binding to JAK2, forming a critical part of the JAK binding epitope (Kershaw2013SOCS3). SOCS3's structure allows it to bind simultaneously to JAK2 and cytokine receptors, forming a ternary complex that enhances its inhibitory function (Kershaw2013SOCS3).

## Function
SOCS3 (Suppressor of Cytokine Signaling 3) is a critical regulator of cytokine signaling pathways, particularly the JAK/STAT pathway, in healthy human cells. It functions as a negative feedback inhibitor by binding to Janus kinases (JAKs) and inhibiting their activity, which prevents the phosphorylation and activation of STAT proteins. This regulation is essential for maintaining balanced immune responses and preventing excessive inflammation (Mahony2016SOCS3; Krebs2001SOCS).

SOCS3 is involved in modulating immune responses by influencing cytokine signaling and T cell differentiation. It inhibits the signaling pathways of various cytokines, including IL-6, IL-10, and IFN-γ, by binding to their receptors and associated JAKs, thereby controlling the activation of STAT proteins such as STAT1, STAT3, and STAT4 (Ilangumaran2004Regulation; Yoshimura2007SOCS). SOCS3 also plays a role in the proteasomal degradation of signaling proteins, acting as an adapter that recruits these proteins to the proteasome for degradation (Krebs2001SOCS).

In the context of immune regulation, SOCS3 is crucial for modulating the differentiation of T helper cells, particularly by inhibiting Th1 responses and regulating Th17 cell differentiation (Chen2006Selective; Ilangumaran2004Regulation). This regulation is vital for preventing autoimmune diseases and maintaining immune homeostasis (Carow2014SOCS3).

## Clinical Significance
The SOCS3 gene plays a significant role in various diseases due to its involvement in cytokine signaling pathways. In cancer, SOCS3 acts as both a tumor suppressor and an onco-immunological biomarker. Its expression levels and genetic alterations, such as gene amplification and mutations, are associated with overall survival and chemotherapy response in cancers like breast, ovarian, glioblastoma, and colorectal cancer (Dai2022SOCS3). SOCS3 is often silenced through DNA methylation in hepatocellular carcinoma, which enhances JAK/STAT signaling and contributes to cancer progression (Niwa2005Methylation). In colorectal cancer, decreased SOCS3 expression may promote tumor development (Igci2012Mutational).

SOCS3 is also implicated in inflammatory and autoimmune diseases. In Graves' ophthalmopathy, higher SOCS3 expression is linked to specific genetic variations, suggesting a role in disease pathogenesis (Yan2015Genetic). In pediatric acute lymphoblastic leukemia, low SOCS3 expression due to promoter methylation leads to continuous activation of the JAK2/STAT3 pathway, promoting tumor cell proliferation (Liu2019Promoter). Additionally, SOCS3 influences immune responses in inflammatory bowel disease by regulating neutrophil and dendritic cell functions (Li2012SOCS3).

## Interactions
SOCS3 interacts with several proteins, playing a crucial role in cytokine signaling regulation. It preferentially binds to the phosphotyrosine-757 (pY757) site on the gp130 receptor subunit, which is also a docking site for the tyrosine phosphatase SHP-2. This interaction is significant for SOCS3's role in inhibiting gp130 signaling (Nicholson2000Suppressor). SOCS3 also interacts with Janus kinases (JAKs), particularly JAK2, where it inhibits kinase activity by blocking substrate binding. The Kinase Inhibitory Region (KIR) of SOCS3 is crucial for this interaction, with specific residues like Phe25 playing a key role (Kershaw2013SOCS3).

SOCS3 forms part of an E3 ubiquitin ligase complex through its interaction with elongin C. This interaction is regulated by tyrosine phosphorylation, which can disrupt the SOCS3-elongin C binding, leading to SOCS3 degradation (Haan2003Tyrosine). SOCS3 also interacts with the insulin-like growth factor-I receptor (IGFIR), as demonstrated through various binding assays (Dey2000Suppressor). Additionally, SOCS3's interaction with MAP1S links it to the microtubule cytoskeleton, which is important for its regulatory function in IL-6 signaling (Zou2008The).


## References


[1. (Ilangumaran2004Regulation) Subburaj Ilangumaran, Sheela Ramanathan, and Robert Rottapel. Regulation of the immune system by socs family adaptor proteins. Seminars in Immunology, 16(6):351–365, December 2004. URL: http://dx.doi.org/10.1016/j.smim.2004.08.015, doi:10.1016/j.smim.2004.08.015. This article has 109 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.smim.2004.08.015)

[2. (Li2012SOCS3) Yi Li, Colin de Haar, Maikel P. Peppelenbosch, and C. Janneke van der Woude. Socs3 in immune regulation of inflammatory bowel disease and inflammatory bowel disease-related cancer. Cytokine & Growth Factor Reviews, 23(3):127–138, June 2012. URL: http://dx.doi.org/10.1016/j.cytogfr.2012.04.005, doi:10.1016/j.cytogfr.2012.04.005. This article has 50 citations.](https://doi.org/10.1016/j.cytogfr.2012.04.005)

[3. (Dai2022SOCS3) Lirui Dai, Yiran Tao, Zimin Shi, Wulong Liang, Weihua Hu, Zhe Xing, Shaolong Zhou, Xuyang Guo, Xudong Fu, and Xinjun Wang. Socs3 acts as an onco-immunological biomarker with value in assessing the tumor microenvironment, pathological staging, histological subtypes, therapeutic effect, and prognoses of several types of cancer. Frontiers in Oncology, May 2022. URL: http://dx.doi.org/10.3389/fonc.2022.881801, doi:10.3389/fonc.2022.881801. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fonc.2022.881801)

[4. (Mahony2016SOCS3) R. Mahony, S. Ahmed, C. Diskin, and N. J. Stevenson. Socs3 revisited: a broad regulator of disease, now ready for therapeutic use? Cellular and Molecular Life Sciences, 73(17):3323–3336, May 2016. URL: http://dx.doi.org/10.1007/s00018-016-2234-x, doi:10.1007/s00018-016-2234-x. This article has 58 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s00018-016-2234-x)

[5. (Zou2008The) Tingting Zou, Lu Ouyang, Lu Chen, Wei Dong, Hong Qiao, Yingle Liu, and Yipeng Qi. The role of microtubule‐associated protein 1s in socs3 regulation of il‐6 signaling. FEBS Letters, 582(29):4015–4022, November 2008. URL: http://dx.doi.org/10.1016/j.febslet.2008.10.055, doi:10.1016/j.febslet.2008.10.055. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.febslet.2008.10.055)

[6. (Babon2006The) Jeffrey J. Babon, Edward J. McManus, Shenggen Yao, David P. DeSouza, Lisa A. Mielke, Naomi S. Sprigg, Tracy A. Willson, Douglas J. Hilton, Nicos A. Nicola, Manuel Baca, Sandra E. Nicholson, and Raymond S. Norton. The structure of socs3 reveals the basis of the extended sh2 domain function and identifies an unstructured insertion that regulates stability. Molecular Cell, 22(2):205–216, April 2006. URL: http://dx.doi.org/10.1016/J.MOLCEL.2006.03.024, doi:10.1016/j.molcel.2006.03.024. This article has 203 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/J.MOLCEL.2006.03.024)

[7. (Kershaw2013SOCS3) Nadia J Kershaw, James M Murphy, Nicholas P D Liau, Leila N Varghese, Artem Laktyushin, Eden L Whitlock, Isabelle S Lucet, Nicos A Nicola, and Jeffrey J Babon. Socs3 binds specific receptor–jak complexes to control cytokine signaling by direct kinase inhibition. Nature Structural & Molecular Biology, 20(4):469–476, March 2013. URL: http://dx.doi.org/10.1038/nsmb.2519, doi:10.1038/nsmb.2519. This article has 230 citations.](https://doi.org/10.1038/nsmb.2519)

[8. (Carow2014SOCS3) Berit Carow and Martin E. Rottenberg. Socs3, a major regulator of infection and inflammation. Frontiers in Immunology, 2014. URL: http://dx.doi.org/10.3389/fimmu.2014.00058, doi:10.3389/fimmu.2014.00058. This article has 365 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2014.00058)

[9. (Babon2008The) Jeffrey J. Babon, Jennifer K. Sabo, Alfreda Soetopo, Shenggen Yao, Michael F. Bailey, Jian-Guo Zhang, Nicos A. Nicola, and Raymond S. Norton. The socs box domain of socs3: structure and interaction with the elonginbc-cullin5 ubiquitin ligase. Journal of Molecular Biology, 381(4):928–940, September 2008. URL: http://dx.doi.org/10.1016/j.jmb.2008.06.038, doi:10.1016/j.jmb.2008.06.038. This article has 126 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.jmb.2008.06.038)

[10. (Niwa2005Methylation) Yasuharu Niwa, Hiroaki Kanda, Yuko Shikauchi, Akio Saiura, Kenichi Matsubara, Tomoyuki Kitagawa, Junji Yamamoto, Takahiko Kubo, and Hirohide Yoshikawa. Methylation silencing of socs-3 promotes cell growth and migration by enhancing jak/stat and fak signalings in human hepatocellular carcinoma. Oncogene, 24(42):6406–6417, June 2005. URL: http://dx.doi.org/10.1038/sj.onc.1208788, doi:10.1038/sj.onc.1208788. This article has 257 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/sj.onc.1208788)

[11. (Haan2003Tyrosine) Serge Haan, Paul Ferguson, Ulrike Sommer, Meena Hiremath, Daniel W. McVicar, Peter C. Heinrich, James A. Johnston, and Nicholas A. Cacalano. Tyrosine phosphorylation disrupts elongin interaction and accelerates socs3 degradation. Journal of Biological Chemistry, 278(34):31972–31979, August 2003. URL: http://dx.doi.org/10.1074/JBC.M303170200, doi:10.1074/jbc.m303170200. This article has 171 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/JBC.M303170200)

[12. (Yan2015Genetic) Ruijia Yan, Junjie Yang, Ping Jiang, Ling Jin, Jing Ma, Rong Huang, Nan Ma, and Fagang Jiang. Genetic variations in the socs3 gene in patients with graves’ ophthalmopathy. Journal of Clinical Pathology, 68(6):448–452, March 2015. URL: http://dx.doi.org/10.1136/jclinpath-2014-202751, doi:10.1136/jclinpath-2014-202751. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1136/jclinpath-2014-202751)

[13. (Liu2019Promoter) Kangkang Liu, Zhengyu Wu, Jinhua Chu, Linhai Yang, and Ningling Wang. Promoter methylation and expression of socs3 affect the clinical outcome of pediatric acute lymphoblastic leukemia by jak/stat pathway. Biomedicine & Pharmacotherapy, 115:108913, July 2019. URL: http://dx.doi.org/10.1016/j.biopha.2019.108913, doi:10.1016/j.biopha.2019.108913. This article has 12 citations.](https://doi.org/10.1016/j.biopha.2019.108913)

[14. (Nicholson2000Suppressor) Sandra E. Nicholson, David De Souza, Louis J. Fabri, Jason Corbin, Tracy A. Willson, Jian-Guo Zhang, Anabel Silva, Maria Asimakis, Alison Farley, Andrew D. Nash, Donald Metcalf, Douglas J. Hilton, Nicos A. Nicola, and Manuel Baca. Suppressor of cytokine signaling-3 preferentially binds to the shp-2-binding site on the shared cytokine receptor subunit gp130. Proceedings of the National Academy of Sciences, 97(12):6493–6498, May 2000. URL: http://dx.doi.org/10.1073/pnas.100135197, doi:10.1073/pnas.100135197. This article has 362 citations.](https://doi.org/10.1073/pnas.100135197)

[15. (Yoshimura2007SOCS) Akihiko Yoshimura, Tetsuji Naka, and Masato Kubo. Socs proteins, cytokine signalling and immune regulation. Nature Reviews Immunology, 7(6):454–465, May 2007. URL: http://dx.doi.org/10.1038/nri2093, doi:10.1038/nri2093. This article has 1221 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/nri2093)

[16. (Krebs2001SOCS) Danielle L. Krebs and Douglas J. Hilton. Socs proteins: negative regulators of cytokine signaling. STEM CELLS, 19(5):378–387, September 2001. URL: http://dx.doi.org/10.1634/stemcells.19-5-378, doi:10.1634/stemcells.19-5-378. This article has 624 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1634/stemcells.19-5-378)

[17. (Igci2012Mutational) Mehri Igci, Ecir Ali Cakmak, Serdar Oztuzcu, Ali Bayram, Ahmet Arslan, Bulent Gogebakan, Yusuf Ziya Igci, Beyhan Cengiz, Esma Ozkara, Celaletdin Camci, and A. Tuncay Demiryurek. Mutational screening of thesocs3gene promoter in metastatic colorectal cancer patients. Genetic Testing and Molecular Biomarkers, 16(12):1395–1400, December 2012. URL: http://dx.doi.org/10.1089/gtmb.2012.0208, doi:10.1089/gtmb.2012.0208. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.1089/gtmb.2012.0208)

[18. (Chen2006Selective) Zhi Chen, Arian Laurence, Yuka Kanno, Margit Pacher-Zavisin, Bing-Mei Zhu, Cristina Tato, Akihiko Yoshimura, Lothar Hennighausen, and John J. O’Shea. Selective regulatory function of socs3 in the formation of il-17-secreting t cells. Proceedings of the National Academy of Sciences, 103(21):8137–8142, May 2006. URL: http://dx.doi.org/10.1073/pnas.0600666103, doi:10.1073/pnas.0600666103. This article has 523 citations.](https://doi.org/10.1073/pnas.0600666103)

[19. (Dey2000Suppressor) Bhakta R. Dey, Richard W. Furlanetto, and Peter Nissley. Suppressor of cytokine signaling (socs)-3 protein interacts with the insulin-like growth factor-i receptor. Biochemical and Biophysical Research Communications, 278(1):38–43, November 2000. URL: http://dx.doi.org/10.1006/BBRC.2000.3762, doi:10.1006/bbrc.2000.3762. This article has 127 citations and is from a peer-reviewed journal.](https://doi.org/10.1006/BBRC.2000.3762)