Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN1ABYR)

• DOT Name: Suppressor of cytokine signaling 5 (SOCS5)
• Synonyms: SOCS-5; Cytokine-inducible SH2 protein 6; CIS-6; Cytokine-inducible SH2-containing protein 5
• Gene Name: SOCS5
• Related Disease:
  Allergic conjunctivitis
  Atopic dermatitis
  Autoimmune disease
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Endometrial carcinoma
  Inflammatory bowel disease
  Influenza
  leukaemia
  Leukemia
  Liver cancer
  Neoplasm
  Nephrotic syndrome
  T-cell acute lymphoblastic leukaemia
  Tuberculosis
  Uveitis
  Advanced cancer
  Chronic obstructive pulmonary disease
  Hepatocellular carcinoma
  Pancreatic cancer
  Asthma
  Diabetic kidney disease
  Myotonic dystrophy type 1
  Type-1 diabetes
  Type-1/2 diabetes
• UniProt ID: SOCS5_HUMAN
• Pfam ID: PF00017 ; PF12610 ; PF07525
• Sequence:
  MDKVGKMWNNFKYRCQNLFGHEGGSRSENVDMNSNRCLSVKEKNISIGDSTPQQQSSPLR
  ENIALQLGLSPSKNSSRRNQNCATEIPQIVEISIEKDNDSCVTPGTRLARRDSYSRHAPW
  GGKKKHSCSTKTQSSLDADKKFGRTRSGLQRRERRYGVSSVHDMDSVSSRTVGSRSLRQR
  LQDTVGLCFPMRTYSKQSKPLFSNKRKIHLSELMLEKCPFPAGSDLAQKWHLIKQHTAPV
  SPHSTFFDTFDPSLVSTEDEEDRLRERRRLSIEEGVDPPPNAQIHTFEATAQVNPLYKLG
  PKLAPGMTEISGDSSAIPQANCDSEEDTTTLCLQSRRQKQRQISGDSHTHVSRQGAWKVH
  TQIDYIHCLVPDLLQITGNPCYWGVMDRYEAEALLEGKPEGTFLLRDSAQEDYLFSVSFR
  RYNRSLHARIEQWNHNFSFDAHDPCVFHSSTVTGLLEHYKDPSSCMFFEPLLTISLNRTF
  PFSLQYICRAVICRCTTYDGIDGLPLPSMLQDFLKEYHYKQKVRVRWLEREPVKAK
• Function: SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. May be a substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Inhibits for instance EGF signaling by mediating the degradation of the EGF receptor/EGFR. Involved in the regulation of T-helper cell differentiation by inhibiting of the IL4 signaling pathway which promotes differentiation into the Th2 phenotype. Can also partially inhibit IL6 and LIF signaling.
• KEGG Pathway:
  JAK-STAT sig.ling pathway (hsa04630)
  Prolactin sig.ling pathway (hsa04917)
• Reactome Pathway:
  Neddylation (R-HSA-8951664)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic conjunctivitis	DISZ5ZJN	Strong	Biomarker	[1]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[2]
Autoimmune disease	DISORMTM	Strong	Biomarker	[3]
Bipolar disorder	DISAM7J2	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[6]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[7]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[8]
Influenza	DIS3PNU3	Strong	Altered Expression	[9]
leukaemia	DISS7D1V	Strong	Altered Expression	[10]
Leukemia	DISNAKFL	Strong	Altered Expression	[10]
Liver cancer	DISDE4BI	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Nephrotic syndrome	DISSPSC2	Strong	Altered Expression	[11]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Posttranslational Modification	[10]
Tuberculosis	DIS2YIMD	Strong	Altered Expression	[12]
Uveitis	DISV0RYS	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[13]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[13]
Pancreatic cancer	DISJC981	moderate	Biomarker	[15]
Asthma	DISW9QNS	Limited	Genetic Variation	[16]
Diabetic kidney disease	DISJMWEY	Limited	Biomarker	[17]
Myotonic dystrophy type 1	DISJC0OX	Limited	Altered Expression	[17]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[18]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[17]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Suppressor of cytokine signaling 5 (SOCS5).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Suppressor of cytokine signaling 5 (SOCS5).	[29]

15 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[23]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[24]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[25]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[26]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[27]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[28]
AMEP	DMFELMQ	Phase 1	AMEP decreases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[32]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[33]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[34]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Suppressor of cytokine signaling 5 (SOCS5).	[30]

References

• [1] The control of allergic conjunctivitis by suppressor of cytokine signaling (SOCS)3 and SOCS5 in a murine model.J Immunol. 2005 Oct 15;175(8):5489-97. doi: 10.4049/jimmunol.175.8.5489.
• [2] Differential expression of mRNA for Th1 and Th2 cytokine-associated transcription factors and suppressors of cytokine signalling in peripheral blood mononuclear cells of patients with atopic dermatitis.Clin Exp Immunol. 2004 Mar;135(3):505-10. doi: 10.1111/j.1365-2249.2004.02405.x.
• [3] SOCS5 mRNA levels in peripheral blood mononuclear cells (PBMC): a potential bio-marker for monitoring response of uveitis patients to Daclizumab therapy.J Autoimmun. 2005 Feb;24(1):39-46. doi: 10.1016/j.jaut.2004.11.006. Epub 2005 Jan 27.
• [4] Sexual dimorphism in up-regulation of suppressors of cytokine signaling genes in patients with bipolar disorder.BMC Psychiatry. 2019 Dec 16;19(1):402. doi: 10.1186/s12888-019-2396-9.
• [5] Suppressor of cytokine signaling (SOCS) genes are downregulated in breast cancer.World J Surg Oncol. 2018 Nov 19;16(1):226. doi: 10.1186/s12957-018-1529-9.
• [6] A novel SOCS5/miR-18/miR-25 axis promotes tumorigenesis in liver cancer.Int J Cancer. 2019 Jan 15;144(2):311-321. doi: 10.1002/ijc.31857. Epub 2018 Nov 9.
• [7] Long noncoding RNA TUSC7 inhibits cell proliferation, migration and invasion by regulating SOCS4 (SOCS5) expression through targeting miR-616 in endometrial carcinoma.Life Sci. 2019 Aug 15;231:116549. doi: 10.1016/j.lfs.2019.116549. Epub 2019 Jun 12.
• [8] Clinical, serologic, and genetic factors associated with pyoderma gangrenosum and erythema nodosum in inflammatory bowel disease patients.Inflamm Bowel Dis. 2014 Mar;20(3):525-33. doi: 10.1097/01.MIB.0000442011.60285.68.
• [9] Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling.Elife. 2017 Feb 14;6:e20444. doi: 10.7554/eLife.20444.
• [10] Epigenetic silencing of SOCS5 potentiates JAK-STAT signaling and progression of T-cell acute lymphoblastic leukemia.Cancer Sci. 2019 Jun;110(6):1931-1946. doi: 10.1111/cas.14021. Epub 2019 May 3.
• [11] SOCS3 and SOCS5 mRNA expressions may predict initial steroid response in nephrotic syndrome children.Folia Histochem Cytobiol. 2011;49(4):719-28. doi: 10.5603/fhc.2011.0096.
• [12] Suppressors of cytokine signaling in tuberculosis.PLoS One. 2017 Apr 21;12(4):e0176377. doi: 10.1371/journal.pone.0176377. eCollection 2017.
• [13] SOCS5 inhibition induces autophagy to impair metastasis in hepatocellular carcinoma cells via the PI3K/Akt/mTOR pathway.Cell Death Dis. 2019 Aug 13;10(8):612. doi: 10.1038/s41419-019-1856-y.
• [14] Upregulation of miR-132 contributes to the pathophysiology of COPD via targeting SOCS5.Exp Mol Pathol. 2018 Dec;105(3):285-292. doi: 10.1016/j.yexmp.2018.10.002. Epub 2018 Oct 4.
• [15] BRM transcriptionally regulates miR-302a-3p to target SOCS5/STAT3 signaling axis to potentiate pancreatic cancer metastasis.Cancer Lett. 2019 May 1;449:215-225. doi: 10.1016/j.canlet.2019.02.031. Epub 2019 Feb 18.
• [16] Opisthorchis felineus liver fluke invasion is an environmental factor modifying genetic risk of atopic bronchial asthma.Acta Trop. 2014 Nov;139:53-6. doi: 10.1016/j.actatropica.2014.07.004. Epub 2014 Jul 11.
• [17] Angpt2 Induces Mesangial Cell Apoptosis through the MicroRNA-33-5p-SOCS5 Loop in Diabetic Nephropathy.Mol Ther Nucleic Acids. 2018 Dec 7;13:543-555. doi: 10.1016/j.omtn.2018.10.003. Epub 2018 Oct 10.
• [18] Association study of polymorphisms in SOCS family genes with type 1 diabetes mellitus.Int J Immunogenet. 2006 Feb;33(1):7-10. doi: 10.1111/j.1744-313X.2006.00563.x.
• [19] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [20] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [21] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [24] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [25] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [26] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [27] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [30] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [31] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [32] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [33] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [34] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.