Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAGXO0N)

• DOT Name: SH2 domain-containing protein 3C (SH2D3C)
• Synonyms: Cas/HEF1-associated signal transducer; Chat-H; Novel SH2-containing protein 3; SH2 domain-containing Eph receptor-binding protein 1; SHEP1
• Gene Name: SH2D3C
• Related Disease:
  Alzheimer disease
  Amyloidosis
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Gastroenteritis
  Chikungunya virus infection
  Neuroblastoma
  Arthritis
  Middle East Respiratory Syndrome (MERS)
• UniProt ID: SH2D3_HUMAN
• PDB ID: 3T6G
• Pfam ID: PF00617 ; PF00017
• Sequence:
  MTEGTKKTSKKFKFFKFKGFGSLSNLPRSFTLRRSSASISRQSHLEPDTFEATQDDMVTV
  PKSPPAYARSSDMYSHMGTMPRPSIKKAQNSQAARQAQEAGPKPNLVPGGVPDPPGLEAA
  KEVMVKATGPLEDTPAMEPNPSAVEVDPIRKPEVPTGDVEEERPPRDVHSERAAGEPEAG
  SDYVKFSKEKYILDSSPEKLHKELEEELKLSSTDLRSHAWYHGRIPREVSETLVQRNGDF
  LIRDSLTSLGDYVLTCRWRNQALHFKINKVVVKAGESYTHIQYLFEQESFDHVPALVRYH
  VGSRKAVSEQSGAIIYCPVNRTFPLRYLEASYGLGQGSSKPASPVSPSGPKGSHMKRRSV
  TMTDGLTADKVTRSDGCPTSTSLPRPRDSIRSCALSMDQIPDLHSPMSPISESPSSPAYS
  TVTRVHAAPAAPSATALPASPVARRSSEPQLCPGSAPKTHGESDKGPHTSPSHTLGKASP
  SPSLSSYSDPDSGHYCQLQPPVRGSREWAATETSSQQARSYGERLKELSENGAPEGDWGK
  TFTVPIVEVTSSFNPATFQSLLIPRDNRPLEVGLLRKVKELLAEVDARTLARHVTKVDCL
  VARILGVTKEMQTLMGVRWGMELLTLPHGRQLRLDLLERFHTMSIMLAVDILGCTGSAEE
  RAALLHKTIQLAAELRGTMGNMFSFAAVMGALDMAQISRLEQTWVTLRQRHTEGAILYEK
  KLKPFLKSLNEGKEGPPLSNTTFPHVLPLITLLECDSAPPEGPEPWGSTEHGVEVVLAHL
  EAARTVAHHGGLYHTNAEVKLQGFQARPELLEVFSTEFQMRLLWGSQGASSSQARRYEKF
  DKVLTALSHKLEPAVRSSEL
• Function: Acts as an adapter protein that mediates cell signaling pathways involved in cellular functions such as cell adhesion and migration, tissue organization, and the regulation of the immune response. Plays a role in integrin-mediated cell adhesion through BCAR1-CRK-RAPGEF1 signaling and activation of the small GTPase RAP1. Promotes cell migration and invasion through the extracellular matrix. Required for marginal zone B-cell development and thymus-independent type 2 immune responses. Mediates migration and adhesion of B cells in the splenic marginal zone via promoting hyperphosphorylation of NEDD9/CASL. Plays a role in CXCL13-induced chemotaxis of B-cells. Plays a role in the migration of olfactory sensory neurons (OSNs) into the forebrain and the innervation of the olfactory bulb by the OSN axons during development. Required for the efficient tyrosine phosphorylation of BCAR1 in OSN axons; [Isoform 1]: Important regulator of chemokine-induced, integrin-mediated T lymphocyte adhesion and migration, acting upstream of RAP1. Required for tissue-specific adhesion of T lymphocytes to peripheral tissues. Required for basal and CXCL2 stimulated serine-threonine phosphorylation of NEDD9. May be involved in the regulation of T-cell receptor-mediated IL2 production through the activation of the JNK pathway in T-cells; [Isoform 2]: May be involved in the BCAR1/CAS-mediated JNK activation pathway.
• Tissue Specificity: .Ubiquitously expressed.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Amyloidosis	DISHTAI2	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Gastroenteritis	DISXQCG5	Strong	Biomarker	[4]
Chikungunya virus infection	DISDXEHY	moderate	Biomarker	[5]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[6]
Arthritis	DIST1YEL	Disputed	Biomarker	[7]
Middle East Respiratory Syndrome (MERS)	DIS5VPYU	Limited	Altered Expression	[8]

2 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 protein 3C (SH2D3C).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of SH2 domain-containing protein 3C (SH2D3C).	[17]

12 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 SH2 domain-containing protein 3C (SH2D3C).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of SH2 domain-containing protein 3C (SH2D3C).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SH2 domain-containing protein 3C (SH2D3C).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of SH2 domain-containing protein 3C (SH2D3C).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SH2 domain-containing protein 3C (SH2D3C).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of SH2 domain-containing protein 3C (SH2D3C).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of SH2 domain-containing protein 3C (SH2D3C).	[13]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of SH2 domain-containing protein 3C (SH2D3C).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of SH2 domain-containing protein 3C (SH2D3C).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of SH2 domain-containing protein 3C (SH2D3C).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of SH2 domain-containing protein 3C (SH2D3C).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of SH2 domain-containing protein 3C (SH2D3C).	[21]

References

• [1] Up-regulation of NSP3 by Oligomeric A Accelerates Neuronal Death Through Cas-independent Rap1A Activation.Neuroscience. 2018 Aug 21;386:182-193. doi: 10.1016/j.neuroscience.2018.06.035. Epub 2018 Jun 30.
• [2] Splice variants and expression patterns of SHEP1, BCAR3 and NSP1, a gene family involved in integrin and receptor tyrosine kinase signaling.Gene. 2007 Apr 15;391(1-2):161-70. doi: 10.1016/j.gene.2006.12.016. Epub 2007 Jan 8.
• [3] AND-34/BCAR3 differs from other NSP homologs in induction of anti-estrogen resistance, cyclin D1 promoter activation and altered breast cancer cell morphology.J Cell Physiol. 2007 Sep;212(3):655-65. doi: 10.1002/jcp.21059.
• [4] Detection of rotavirus RNA and antigens in serum and cerebrospinal fluid samples from diarrheic children with seizures.Jpn J Infect Dis. 2009 Jul;62(4):279-83.
• [5] The Host DHX9 DExH-Box Helicase Is Recruited to Chikungunya Virus Replication Complexes for Optimal Genomic RNA Translation.J Virol. 2019 Feb 5;93(4):e01764-18. doi: 10.1128/JVI.01764-18. Print 2019 Feb 15.
• [6] Role of p53 in the regulation of irradiation-induced apoptosis in neuroblastoma cells.Mol Genet Metab. 1998 Oct;65(2):155-64. doi: 10.1006/mgme.1998.2747.
• [7] Real-time polymerase chain reaction for diagnosis and quantitation of negative strand of chikungunya virus.Diagn Microbiol Infect Dis. 2013 Oct;77(2):133-7. doi: 10.1016/j.diagmicrobio.2013.06.018. Epub 2013 Jul 23.
• [8] Expression and Cleavage of Middle East Respiratory Syndrome Coronavirus nsp3-4 Polyprotein Induce the Formation of Double-Membrane Vesicles That Mimic Those Associated with Coronaviral RNA Replication.mBio. 2017 Nov 21;8(6):e01658-17. doi: 10.1128/mBio.01658-17.
• [9] 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.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [13] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [14] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [15] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [16] 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.
• [17] 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.
• [18] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [19] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [20] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [21] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.