Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJZO2CI)

• DOT Name: SH2B adapter protein 1 (SH2B1)
• Synonyms: Pro-rich, PH and SH2 domain-containing signaling mediator; PSM; SH2 domain-containing protein 1B
• Gene Name: SH2B1
• Related Disease:
  Non-insulin dependent diabetes
  Advanced cancer
  Alzheimer disease
  Amyloidosis
  Aplastic anemia
  Atopic dermatitis
  Atrial fibrillation
  Colorectal carcinoma
  Dementia
  High blood pressure
  Hyperinsulinemia
  Liver cirrhosis
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Malignant soft tissue neoplasm
  Niemann-Pick disease, type C1
  Prostate adenocarcinoma
  Prostate cancer
  Prostate neoplasm
  Retinoblastoma
  Sarcoma
  Type-1/2 diabetes
  Bipolar disorder
  Inflammatory bowel disease
  Neurodevelopmental disorder
  Non-small-cell lung cancer
  Severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency
  Asthma
  Chronic obstructive pulmonary disease
  Coronary heart disease
  Gastric cancer
  Hepatocellular carcinoma
  Hyperglycemia
  Myocardial infarction
  Neoplasm
  Neuroblastoma
  Prostate carcinoma
  Stomach cancer
• UniProt ID: SH2B1_HUMAN
• PDB ID: 5W3R
• Pfam ID: PF00169 ; PF08916 ; PF00017
• Sequence:
  MNGAPSPEDGASPSSPPLPPPPPPSWREFCESHARAAALDFARRFRLYLASHPQYAGPGA
  EAAFSRRFAELFLQHFEAEVARASGSLSPPILAPLSPGAEISPHDLSLESCRVGGPLAVL
  GPSRSSEDLAGPLPSSVSSSSTTSSKPKLKKRFSLRSVGRSVRGSVRGILQWRGTVDPPS
  SAGPLETSSGPPVLGGNSNSNSSGGAGTVGRGLVSDGTSPGERWTHRFERLRLSRGGGAL
  KDGAGMVQREELLSFMGAEEAAPDPAGVGRGGGVAGPPSGGGGQPQWQKCRLLLRSEGEG
  GGGSRLEFFVPPKASRPRLSIPCSSITDVRTTTALEMPDRENTFVVKVEGPSEYIMETVD
  AQHVKAWVSDIQECLSPGPCPATSPRPMTLPLAPGTSFLTRENTDSLELSCLNHSESLPS
  QDLLLGPSESNDRLSQGAYGGLSDRPSASISPSSASIAASHFDSMELLPPELPPRIPIEE
  GPPTGTVHPLSAPYPPLDTPETATGSFLFQGEPEGGEGDQPLSGYPWFHGMLSRLKAAQL
  VLTGGTGSHGVFLVRQSETRRGEYVLTFNFQGKAKHLRLSLNEEGQCRVQHLWFQSIFDM
  LEHFRVHPIPLESGGSSDVVLVSYVPSSQRQQEPTTSHDPPQPPEPPSWTDPPQPGAEEA
  SRAPEVAAAAAAAAKERQEKEKAGGGGVPEELVPVVELVPVVELEEAIAPGSEAQGAGSG
  GDAGVPPMVQLQQSPLGGDGEEGGHPRAINNQYSFV
• Function: Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases, including the receptors of insulin (INS), insulin-like growth factor I (IGF1), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), platelet-derived growth factor (PDGF) and fibroblast growth factors (FGFs). In growth hormone (GH) signaling, autophosphorylated ('Tyr-813') JAK2 recruits SH2B1, which in turn is phosphorylated by JAK2 on tyrosine residues. These phosphotyrosines form potential binding sites for other signaling proteins. GH also promotes serine/threonine phosphorylation of SH2B1 and these phosphorylated residues may serve to recruit other proteins to the GHR-JAK2-SH2B1 complexes, such as RAC1. In leptin (LEP) signaling, binds to and potentiates the activation of JAK2 by globally enhancing downstream pathways. In response to leptin, binds simultaneously to both, JAK2 and IRS1 or IRS2, thus mediating formation of a complex of JAK2, SH2B1 and IRS1 or IRS2. Mediates tyrosine phosphorylation of IRS1 and IRS2, resulting in activation of the PI 3-kinase pathway. Acts as a positive regulator of NGF-mediated activation of the Akt/Forkhead pathway; prolongs NGF-induced phosphorylation of AKT1 on 'Ser-473' and AKT1 enzymatic activity. Enhances the kinase activity of the cytokine receptor-associated tyrosine kinase JAK2 and of other receptor tyrosine kinases, such as FGFR3 and NTRK1. For JAK2, the mechanism seems to involve dimerization of both, SH2B1 and JAK2. Enhances RET phosphorylation and kinase activity. Isoforms seem to be differentially involved in IGF-I and PDGF-induced mitogenesis.
• Tissue Specificity: Widely expressed with highest levels in skeletal muscle and ovary.
• KEGG Pathway: Neurotrophin sig.ling pathway (hsa04722)
• Reactome Pathway: Factors involved in megakaryocyte development and platelet production (R-HSA-983231)

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Amyloidosis	DISHTAI2	Strong	Biomarker	[4]
Aplastic anemia	DISJRSC0	Strong	Biomarker	[5]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[6]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Dementia	DISXL1WY	Strong	Biomarker	[4]
High blood pressure	DISY2OHH	Strong	Biomarker	[8]
Hyperinsulinemia	DISIDWT6	Strong	Genetic Variation	[9]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[8]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[10]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[11]
Niemann-Pick disease, type C1	DIS9HUE3	Strong	Biomarker	[12]
Prostate adenocarcinoma	DISBZYU8	Strong	Biomarker	[13]
Prostate cancer	DISF190Y	Strong	Biomarker	[14]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[13]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[15]
Sarcoma	DISZDG3U	Strong	Biomarker	[11]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[8]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[16]
Inflammatory bowel disease	DISGN23E	moderate	Genetic Variation	[17]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[18]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Biomarker	[19]
Severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency	DIST2XAU	Moderate	Autosomal dominant	[20]
Asthma	DISW9QNS	Limited	Biomarker	[21]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[22]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[23]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[24]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[25]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[26]
Myocardial infarction	DIS655KI	Limited	Genetic Variation	[23]
Neoplasm	DISZKGEW	Limited	Biomarker	[10]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[24]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[14]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of SH2B adapter protein 1 (SH2B1).	[27]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of SH2B adapter protein 1 (SH2B1).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of SH2B adapter protein 1 (SH2B1).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of SH2B adapter protein 1 (SH2B1).	[28]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of SH2B adapter protein 1 (SH2B1).	[30]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of SH2B adapter protein 1 (SH2B1).	[31]

References

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• [2] New perspective on SH2B1: An accelerator of cancer progression.Biomed Pharmacother. 2020 Jan;121:109651. doi: 10.1016/j.biopha.2019.109651. Epub 2019 Nov 15.
• [3] The Protective Effects of PSM-04 Against Beta Amyloid-Induced Neurotoxicity in Primary Cortical Neurons and an Animal Model of Alzheimer's Disease.Front Pharmacol. 2019 Jan 24;10:2. doi: 10.3389/fphar.2019.00002. eCollection 2019.
• [4] SH2B1 is Involved in the Accumulation of Amyloid-42 in Alzheimer's Disease.J Alzheimers Dis. 2017;55(2):835-847. doi: 10.3233/JAD-160233.
• [5] Aplastic Anemia and Risk of Incident Atrial Fibrillation- A Nationwide Cohort Study.Circ J. 2018 Apr 25;82(5):1279-1285. doi: 10.1253/circj.CJ-17-0519. Epub 2018 Feb 16.
• [6] Phosphodiesterase 4D, miR-203 and selected cytokines in the peripheral blood are associated with canine atopic dermatitis.PLoS One. 2019 Jun 21;14(6):e0218670. doi: 10.1371/journal.pone.0218670. eCollection 2019.
• [7] Hsa_circ_0136666 promotes the proliferation and invasion of colorectal cancer through miR-136/SH2B1 axis.J Cell Physiol. 2019 May;234(5):7247-7256. doi: 10.1002/jcp.27482. Epub 2018 Oct 28.
• [8] Hepatitis B and renal function: A matched study comparing non-hepatitis B, untreated, treated and cirrhotic hepatitis patients.Liver Int. 2019 Apr;39(4):655-666. doi: 10.1111/liv.14009. Epub 2018 Dec 18.
• [9] The SH2B1 obesity locus and abnormal glucose homeostasis: lack of evidence for association from a meta-analysis in individuals of European ancestry.Nutr Metab Cardiovasc Dis. 2013 Nov;23(11):1043-9. doi: 10.1016/j.numecd.2013.05.001. Epub 2013 Oct 5.
• [10] SH2B1 promotes epithelial-mesenchymal transition through the IRS1/-catenin signaling axis in lung adenocarcinoma.Mol Carcinog. 2018 May;57(5):640-652. doi: 10.1002/mc.22788. Epub 2018 Feb 20.
• [11] Functional characterization of obesity-associated variants involving the and isoforms of human SH2B1.Endocrinology. 2014 Sep;155(9):3219-26. doi: 10.1210/en.2014-1264. Epub 2014 Jun 27.
• [12] Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population.J Hum Genet. 2009 Dec;54(12):727-31. doi: 10.1038/jhg.2009.106. Epub 2009 Oct 23.
• [13] Prostate-specific membrane antigen.Prostate. 1997 Jul 1;32(2):140-8. doi: 10.1002/(sici)1097-0045(19970701)32:2<140::aid-pros9>3.0.co;2-q.
• [14] Differences in urinary proteins related to surgical margin status after radical prostatectomy.Oncol Rep. 2015 Dec;34(6):3247-55. doi: 10.3892/or.2015.4322.
• [15] Activation of the retinoblastoma tumor suppressor mediates cell cycle inhibition and cell death in specific cervical cancer cell lines.Mol Carcinog. 2009 Jan;48(1):45-55. doi: 10.1002/mc.20456.
• [16] Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI.Transl Psychiatry. 2019 Nov 21;9(1):315. doi: 10.1038/s41398-019-0652-x.
• [17] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [18] Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother.Eur J Hum Genet. 2012 May;20(5):540-6. doi: 10.1038/ejhg.2011.244. Epub 2012 Jan 11.
• [19] A Robust 8-Gene Prognostic Signature for Early-Stage Non-small Cell Lung Cancer.Front Oncol. 2019 Jul 31;9:693. doi: 10.3389/fonc.2019.00693. eCollection 2019.
• [20] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [21] A common 16p11.2 inversion underlies the joint susceptibility to asthma and obesity.Am J Hum Genet. 2014 Mar 6;94(3):361-72. doi: 10.1016/j.ajhg.2014.01.015. Epub 2014 Feb 20.
• [22] Improving recruitment to a study of telehealth management for COPD: a cluster randomised controlled 'study within a trial' (SWAT) of a multimedia information resource.Trials. 2019 Jul 24;20(1):453. doi: 10.1186/s13063-019-3496-z.
• [23] The SH2B1 obesity locus is associated with myocardial infarction in diabetic patients and with NO synthase activity in endothelial cells.Atherosclerosis. 2011 Dec;219(2):667-72. doi: 10.1016/j.atherosclerosis.2011.08.019. Epub 2011 Aug 19.
• [24] Circulating SH2B1 is associated with an increased risk of gastric cancer.Oncol Lett. 2018 May;15(5):7305-7311. doi: 10.3892/ol.2018.8196. Epub 2018 Mar 7.
• [25] Prognostic importance of bile duct invasion in surgical resection with curative intent for hepatocellular carcinoma using PSM analysis.Oncol Lett. 2018 Sep;16(3):3593-3602. doi: 10.3892/ol.2018.9108. Epub 2018 Jul 10.
• [26] SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins.Diabetes. 2009 Sep;58(9):2039-47. doi: 10.2337/db08-1388. Epub 2009 Jun 19.
• [27] 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.
• [28] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [29] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [30] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [31] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [32] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.