Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU1J2KH)

DOT Name	Sharpin (SHARPIN)
Synonyms	Shank-associated RH domain-interacting protein; Shank-interacting protein-like 1; hSIPL1
Gene Name	SHARPIN
Related Disease	Cervical cancer ( ) Cervical carcinoma ( ) Esophageal cancer ( ) Adenocarcinoma ( ) Advanced cancer ( ) Atopic dermatitis ( ) Branchio-oto-renal syndrome ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Dermatitis ( ) Epithelial ovarian cancer ( ) Estrogen-receptor positive breast cancer ( ) Incontinentia pigmenti ( ) Inflammation ( ) Liver cancer ( ) Liver cirrhosis ( ) Lung cancer ( ) Lung carcinoma ( ) Mycosis fungoides ( ) Ovarian cancer ( ) Ovarian neoplasm ( ) Prostate cancer ( ) Prostate carcinoma ( ) Psoriasis ( ) Pyogenic bacterial infections due to MyD88 deficiency ( ) Skin carcinoma ( ) Neoplasm ( ) Breast cancer ( ) Breast carcinoma ( ) Immune system disorder ( ) Melanoma ( )
UniProt ID	SHRPN_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	4EMO; 5X0W
Pfam ID	PF16764
Sequence	MAPPAGGAAAAASDLGSAAVLLAVHAAVRPLGAGPDAEAQLRRLQLSADPERPGRFRLEL LGAGPGAVNLEWPLESVSYTIRGPTQHELQPPPGGPGTLSLHFLNPQEAQRWAVLVRGAT VEGQNGSKSNSPPALGPEACPVSLPSPPEASTLKGPPPEADLPRSPGNLTEREELAGSLA RAIAGGDEKGAAQVAAVLAQHRVALSVQLQEACFPPGPIRLQVTLEDAASAASAASSAHV ALQVHPHCTVAALQEQVFSELGFPPAVQRWVIGRCLCVPERSLASYGVRQDGDPAFLYLL SAPREAPATGPSPQHPQKMDGELGRLFPPSLGLPPGPQPAASSLPSPLQPSWSCPSCTFI NAPDRPGCEMCSTQRPCTWDPLAAAST
Function	Component of the LUBAC complex which conjugates linear polyubiquitin chains in a head-to-tail manner to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. The LUBAC complex is also involved in innate immunity by conjugating linear polyubiquitin chains at the surface of bacteria invading the cytosol to form the ubiquitin coat surrounding bacteria. LUBAC is not able to initiate formation of the bacterial ubiquitin coat, and can only promote formation of linear polyubiquitins on pre-existing ubiquitin. The bacterial ubiquitin coat acts as an 'eat-me' signal for xenophagy and promotes NF-kappa-B activation. Together with OTULIN, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis.
Tissue Specificity	Highly expressed in skeletal muscle and placenta and at lower levels in brain, heart, colon without mucosa, thymus, spleen, kidney, liver, small intestine, lung and peripheral blood leukocytes. Up-regulated in various tumor tissues such as kidney, liver, ovary and pancreas tumors.
KEGG Pathway	Necroptosis (hsa04217 ) NOD-like receptor sig.ling pathway (hsa04621 ) Shigellosis (hsa05131 )
Reactome Pathway	Regulation of TNFR1 signaling (R-HSA-5357905 ) TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956 ) Neurexins and neuroligins (R-HSA-6794361 ) TNFR1-induced proapoptotic signaling (R-HSA-5357786 )

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Cervical cancer	DISFSHPF	Definitive	Altered Expression	[1]
Cervical carcinoma	DIST4S00	Definitive	Altered Expression	[1]
Esophageal cancer	DISGB2VN	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[5]
Branchio-oto-renal syndrome	DISIPQ53	Strong	Genetic Variation	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[3]
Dermatitis	DISY5SZC	Strong	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[3]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[8]
Incontinentia pigmenti	DIS0ALLE	Strong	Biomarker	[9]
Inflammation	DISJUQ5T	Strong	Genetic Variation	[7]
Liver cancer	DISDE4BI	Strong	Altered Expression	[3]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[10]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Mycosis fungoides	DIS62RB8	Strong	Altered Expression	[11]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[3]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[3]
Psoriasis	DIS59VMN	Strong	Biomarker	[7]
Pyogenic bacterial infections due to MyD88 deficiency	DIS9697Z	Strong	Biomarker	[7]
Skin carcinoma	DISUZREN	Strong	Genetic Variation	[12]
Neoplasm	DISZKGEW	Disputed	Biomarker	[13]
Breast cancer	DIS7DPX1	Limited	Biomarker	[14]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[14]
Immune system disorder	DISAEGPH	Limited	Biomarker	[15]
Melanoma	DIS1RRCY	Limited	Biomarker	[13]
------------------------------------------------------------------------------------


⏷ Show the Full List of 30 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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 Sharpin (SHARPIN).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Sharpin (SHARPIN).	[19]
------------------------------------------------------------------------------------

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Sharpin (SHARPIN).	[17]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Sharpin (SHARPIN).	[18]
------------------------------------------------------------------------------------

References

1	Shank-interacting protein-like 1 promotes tumorigenesis via PTEN inhibition in human tumor cells.J Clin Invest. 2010 Jun;120(6):2094-108. doi: 10.1172/JCI40778. Epub 2010 May 10.
2	Shank-associated RH domain-interacting protein expression is upregulated in entodermal and mesodermal cancer or downregulated in ectodermal malignancy.Oncol Lett. 2018 Dec;16(6):7180-7188. doi: 10.3892/ol.2018.9514. Epub 2018 Sep 27.
3	Elevation of SHARPIN Protein Levels in Prostate Adenocarcinomas Promotes Metastasis and Impairs Patient Survivals.Prostate. 2017 May;77(7):718-728. doi: 10.1002/pros.23302. Epub 2017 Feb 23.
4	(68)Ga-DOTA-E[c(RGDfK)](2) PET Imaging of SHARPIN-Regulated Integrin Activity in Mice.J Nucl Med. 2019 Oct;60(10):1380-1387. doi: 10.2967/jnumed.118.222026. Epub 2019 Mar 8.
5	Profiling of epidermal lipids in a mouse model of dermatitis: Identification of potential biomarkers.PLoS One. 2018 Apr 26;13(4):e0196595. doi: 10.1371/journal.pone.0196595. eCollection 2018.
6	Sipl1 and Rbck1 are novel Eya1-binding proteins with a role in craniofacial development.Mol Cell Biol. 2010 Dec;30(24):5764-75. doi: 10.1128/MCB.01645-09. Epub 2010 Oct 18.
7	Innate immune adaptor MyD88 deficiency prevents skin inflammation in SHARPIN-deficient mice.Cell Death Differ. 2019 Mar;26(4):741-750. doi: 10.1038/s41418-018-0159-7. Epub 2018 Jul 23.
8	A role of SIPL1/SHARPIN in promoting resistance to hormone therapy in breast cancer.Biochim Biophys Acta Mol Basis Dis. 2018 Mar;1864(3):735-745. doi: 10.1016/j.bbadis.2017.12.018. Epub 2017 Dec 14.
9	Lack of interaction between NEMO and SHARPIN impairs linear ubiquitination and NF-B activation and leads to incontinentia pigmenti.J Allergy Clin Immunol. 2017 Dec;140(6):1671-1682.e2. doi: 10.1016/j.jaci.2016.11.056. Epub 2017 Feb 27.
10	Reduced SHARPIN and LUBAC Formation May Contribute to CCl? or Acetaminophen-Induced Liver Cirrhosis in Mice.Int J Mol Sci. 2017 Feb 4;18(2):326. doi: 10.3390/ijms18020326.
11	SHARPIN overexpression promotes TAK1 expression and activates JNKs and NF-B pathway in Mycosis Fungoides.Exp Dermatol. 2019 Nov;28(11):1279-1288. doi: 10.1111/exd.14026. Epub 2019 Sep 10.
12	Aberrant expression and high-frequency mutations of SHARPIN in nonmelanoma skin cancer.Exp Ther Med. 2019 Apr;17(4):2746-2756. doi: 10.3892/etm.2019.7261. Epub 2019 Feb 12.
13	SHARPIN Promotes Melanoma Progression viaRap1 Signaling Pathway.J Invest Dermatol. 2020 Feb;140(2):395-403.e6. doi: 10.1016/j.jid.2019.07.696. Epub 2019 Aug 8.
14	Atypical ubiquitin-binding protein SHARPIN promotes breast cancer progression.Biomed Pharmacother. 2019 Nov;119:109414. doi: 10.1016/j.biopha.2019.109414. Epub 2019 Sep 10.
15	Structural Insights into SHARPIN-Mediated Activation of HOIP for the Linear Ubiquitin Chain Assembly.Cell Rep. 2017 Oct 3;21(1):27-36. doi: 10.1016/j.celrep.2017.09.031.
16	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.
17	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.
18	Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways. Int J Mol Sci. 2019 Nov 30;20(23):6039. doi: 10.3390/ijms20236039.
19	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.