Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF2HSC0)

• DOT Name: SH2 domain-containing adapter protein B (SHB)
• Gene Name: SHB
• Related Disease:
  Acute myelogenous leukaemia
  leukaemia
  Leukemia
  Melanoma
  Promyelocytic leukaemia
  T-cell leukaemia
  Neoplasm
• UniProt ID: SHB_HUMAN
• Pfam ID: PF00017
• Sequence:
  MAKWLNKYFSLGNSKTKSPPQPPRPDYREQRRRGERPSQPPQAVPQASSAASASCGPATA
  SCFSASSGSLPDDSGSTSDLIRAYRAQKERDFEDPYNGPGSSLRKLRAMCRLDYCGGSGE
  PGGVQRAFSASSASGAAGCCCASSGAGAAASSSSSSGSPHLYRSSSERRPATPAEVRYIS
  PKHRLIKVESAAGGGAGDPLGGACAGGRTWSPTACGGKKLLNKCAASAAEESGAGKKDKV
  TIADDYSDPFDAKNDLKSKAGKGESAGYMEPYEAQRIMTEFQRQESVRSQHKGIQLYDTP
  YEPEGQSVDSDSESTVSPRLRESKLPQDDDRPADEYDQPWEWNRVTIPALAAQFNGNEKR
  QSSPSPSRDRRRQLRAPGGGFKPIKHGSPEFCGILGERVDPAVPLEKQIWYHGAISRGDA
  ENLLRLCKECSYLVRNSQTSKHDYSLSLRSNQGFMHMKLAKTKEKYVLGQNSPPFDSVPE
  VIHYYTTRKLPIKGAEHLSLLYPVAVRTL
• Function: Adapter protein which regulates several signal transduction cascades by linking activated receptors to downstream signaling components. May play a role in angiogenesis by regulating FGFR1, VEGFR2 and PDGFR signaling. May also play a role in T-cell antigen receptor/TCR signaling, interleukin-2 signaling, apoptosis and neuronal cells differentiation by mediating basic-FGF and NGF-induced signaling cascades. May also regulate IRS1 and IRS2 signaling in insulin-producing cells.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: VEGFA-VEGFR2 Pathway (R-HSA-4420097)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
leukaemia	DISS7D1V	Strong	Biomarker	[2]
Leukemia	DISNAKFL	Strong	Biomarker	[2]
Melanoma	DIS1RRCY	Strong	Biomarker	[3]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[1]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[3]

4 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 SH2 domain-containing adapter protein B (SHB).	[4]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of SH2 domain-containing adapter protein B (SHB).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of SH2 domain-containing adapter protein B (SHB).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of SH2 domain-containing adapter protein B (SHB).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of SH2 domain-containing adapter protein B (SHB).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SH2 domain-containing adapter protein B (SHB).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SH2 domain-containing adapter protein B (SHB).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of SH2 domain-containing adapter protein B (SHB).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of SH2 domain-containing adapter protein B (SHB).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of SH2 domain-containing adapter protein B (SHB).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of SH2 domain-containing adapter protein B (SHB).	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of SH2 domain-containing adapter protein B (SHB).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of SH2 domain-containing adapter protein B (SHB).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of SH2 domain-containing adapter protein B (SHB).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of SH2 domain-containing adapter protein B (SHB).	[7]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of SH2 domain-containing adapter protein B (SHB).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of SH2 domain-containing adapter protein B (SHB).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of SH2 domain-containing adapter protein B (SHB).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of SH2 domain-containing adapter protein B (SHB).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of SH2 domain-containing adapter protein B (SHB).	[20]

References

• [1] Tumor SHB gene expression affects disease characteristics in human acute myeloid leukemia.Tumour Biol. 2017 Oct;39(10):1010428317720643. doi: 10.1177/1010428317720643.
• [2] Disparate effects of Shb gene deficiency on disease characteristics in murine models of myeloid, B-cell, and T-cell leukemia.Tumour Biol. 2018 Apr;40(4):1010428318771472. doi: 10.1177/1010428318771472.
• [3] The Cdh5-CreERT2 transgene causes conditional Shb gene deletion in hematopoietic cells with consequences for immune cell responses to tumors.Sci Rep. 2019 May 17;9(1):7548. doi: 10.1038/s41598-019-44039-z.
• [4] 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.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Gene expression profiles with activation of the estrogen receptor alpha-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor. Cancer Res. 2002 Aug 1;62(15):4419-26.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] 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.
• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [17] 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.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.