Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSUYI9A)

DOT Name	E3 ubiquitin-protein ligase CHIP (STUB1)
Synonyms	EC 2.3.2.27; Antigen NY-CO-7; CLL-associated antigen KW-8; Carboxy terminus of Hsp70-interacting protein; RING-type E3 ubiquitin transferase CHIP; STIP1 homology and U box-containing protein 1
Gene Name	STUB1
Related Disease	Acute myelogenous leukaemia ( ) Acute myocardial infarction ( ) Alzheimer disease ( ) Amyotrophic lateral sclerosis ( ) Arteriosclerosis ( ) Atherosclerosis ( ) Attention deficit hyperactivity disorder ( ) Autosomal recessive spinocerebellar ataxia 16 ( ) Breast cancer ( ) Breast neoplasm ( ) Cardiac arrest ( ) Cardiac failure ( ) Cerebellar ataxia ( ) Cerebellar ataxia-hypogonadism syndrome ( ) Chronic kidney disease ( ) Colorectal carcinoma ( ) Congestive heart failure ( ) Epithelial ovarian cancer ( ) Head and neck cancer ( ) Head and neck carcinoma ( ) High blood pressure ( ) Hypogonadism ( ) Lung cancer ( ) Lung carcinoma ( ) Metabolic disorder ( ) Movement disorder ( ) Myelodysplastic syndrome ( ) Neoplasm ( ) Non-insulin dependent diabetes ( ) Non-small-cell lung cancer ( ) Ovarian cancer ( ) Pancreatic cancer ( ) Polycystic ovarian syndrome ( ) Primary myelofibrosis ( ) Prostate cancer ( ) Prostate carcinoma ( ) Schizophrenia ( ) Small lymphocytic lymphoma ( ) Spinocerebellar ataxia 48 ( ) Systemic lupus erythematosus ( ) Breast carcinoma ( ) leukaemia ( ) Leukemia ( ) Metastatic malignant neoplasm ( ) Plasma cell myeloma ( ) Advanced cancer ( ) Gastric cancer ( ) Parkinson disease ( ) Stomach cancer ( ) Thyroid gland papillary carcinoma ( )
UniProt ID	CHIP_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	4KBQ; 6EFK; 6NSV; 7TB1; 8EHZ; 8EI0; 8F14; 8F15; 8F16; 8F17; 8FYU
EC Number	2.3.2.27
Pfam ID	PF12895 ; PF18391 ; PF04564
Sequence	MKGKEEKEGGARLGAGGGSPEKSPSAQELKEQGNRLFVGRKYPEAAACYGRAITRNPLVA VYYTNRALCYLKMQQHEQALADCRRALELDGQSVKAHFFLGQCQLEMESYDEAIANLQRA YSLAKEQRLNFGDDIPSALRIAKKKRWNSIEERRIHQESELHSYLSRLIAAERERELEEC QRNHEGDEDDSHVRAQQACIEAKHDKYMADMDELFSQVDEKRKKRDIPDYLCGKISFELM REPCITPSGITYDRKDIEEHLQRVGHFDPVTRSPLTQEQLIPNLAMKEVIDAFISENGWV EDY
Function	E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation. Plays a role in the maintenance of mitochondrial morphology and promotes mitophagic removal of dysfunctional mitochondria; thereby acts as a protector against apoptosis in response to cellular stress. Negatively regulates vascular smooth muscle contraction, via degradation of the transcriptional activator MYOCD and subsequent loss of transcription of genes involved in vascular smooth muscle contraction. Promotes survival and proliferation of cardiac smooth muscle cells via ubiquitination and degradation of FOXO1, resulting in subsequent repression of FOXO1-mediated transcription of pro-apoptotic genes. Ubiquitinates ICER-type isoforms of CREM and targets them for proteasomal degradation, thereby acts as a positive effector of MAPK/ERK-mediated inhibition of apoptosis in cardiomyocytes. Inhibits lipopolysaccharide-induced apoptosis and hypertrophy in cardiomyocytes, via ubiquitination and subsequent proteasomal degradation of NFATC3. Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. Ubiquitinates NOS1 in concert with Hsp70 and Hsp40. Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90. Ubiquitinates CHRNA3 targeting it for endoplasmic reticulum-associated degradation in cortical neurons, as part of the STUB1-VCP-UBXN2A complex. Ubiquitinates and promotes ESR1 proteasomal degradation in response to age-related circulating estradiol (17-beta-estradiol/E2) decline, thereby promotes neuronal apoptosis in response to ischemic reperfusion injury. Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation. Mediates polyubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB-degradation by the proteasome. Mediates polyubiquitination of CYP3A4. Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation. Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and promotes ubiquitin-mediated protein degradation. Negatively regulates the suppressive function of regulatory T-cells (Treg) during inflammation by mediating the ubiquitination and degradation of FOXP3 in a HSPA1A/B-dependent manner. Catalyzes monoubiquitination of SIRT6, preventing its degradation by the proteasome. Likely mediates polyubiquitination and down-regulates plasma membrane expression of PD-L1/CD274, an immune inhibitory ligand critical for immune tolerance to self and antitumor immunity. Negatively regulates TGF-beta signaling by modulating the basal level of SMAD3 via ubiquitin-mediated degradation. Plays a role in the degradation of TP53. Mediates ubiquitination of RIPK3 leading to its subsequent proteasome-dependent degradation. May regulate myosin assembly in striated muscles together with UBE4B and VCP/p97 by targeting myosin chaperone UNC45B for proteasomal degradation.
Tissue Specificity	Expressed in differentiated myotubes (at protein level) . Highly expressed in skeletal muscle, heart, pancreas, brain and placenta . Detected in kidney, liver and lung .
KEGG Pathway	Ubiquitin mediated proteolysis (hsa04120 ) Protein processing in endoplasmic reticulum (hsa04141 )
Reactome Pathway	RIPK1-mediated regulated necrosis (R-HSA-5213460 ) Regulation of TNFR1 signaling (R-HSA-5357905 ) Regulation of necroptotic cell death (R-HSA-5675482 ) Downregulation of ERBB2 signaling (R-HSA-8863795 ) Regulation of RUNX2 expression and activity (R-HSA-8939902 ) Regulation of PTEN stability and activity (R-HSA-8948751 ) Antigen processing (R-HSA-983168 ) Downregulation of TGF-beta receptor signaling (R-HSA-2173788 )

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[6]
Autosomal recessive spinocerebellar ataxia 16	DISZDE2N	Strong	Autosomal recessive	[7]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[8]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[8]
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[9]
Cardiac failure	DISDC067	Strong	Biomarker	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[9]
Cerebellar ataxia-hypogonadism syndrome	DISUEBFP	Strong	Biomarker	[10]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[12]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[13]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[14]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[14]
High blood pressure	DISY2OHH	Strong	Biomarker	[5]
Hypogonadism	DISICMNI	Strong	Genetic Variation	[15]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[16]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[17]
Movement disorder	DISOJJ2D	Strong	Biomarker	[18]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[19]
Neoplasm	DISZKGEW	Strong	Biomarker	[20]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[21]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[16]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[22]
Pancreatic cancer	DISJC981	Strong	Posttranslational Modification	[23]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[24]
Primary myelofibrosis	DIS6L0CN	Strong	Genetic Variation	[25]
Prostate cancer	DISF190Y	Strong	Biomarker	[26]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[26]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[27]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[28]
Spinocerebellar ataxia 48	DISEXLU4	Strong	Autosomal dominant	[7]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[29]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[8]
leukaemia	DISS7D1V	moderate	Biomarker	[30]
Leukemia	DISNAKFL	moderate	Biomarker	[30]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[31]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[32]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[33]
Gastric cancer	DISXGOUK	Limited	Biomarker	[34]
Parkinson disease	DISQVHKL	Limited	Biomarker	[35]
Stomach cancer	DISKIJSX	Limited	Biomarker	[34]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[36]
------------------------------------------------------------------------------------


⏷ Show the Full List of 50 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 E3 ubiquitin-protein ligase CHIP (STUB1).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase CHIP (STUB1).	[42]
------------------------------------------------------------------------------------

6 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 E3 ubiquitin-protein ligase CHIP (STUB1).	[38]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase CHIP (STUB1).	[39]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase CHIP (STUB1).	[40]
Selenium	DM25CGV	Approved	Selenium increases the expression of E3 ubiquitin-protein ligase CHIP (STUB1).	[41]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of E3 ubiquitin-protein ligase CHIP (STUB1).	[41]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase CHIP (STUB1).	[43]
------------------------------------------------------------------------------------


⏷ Show the Full List of 6 Drug(s)

References

1	Next Generation Sequencing in AML-On the Way to Becoming a New Standard for Treatment Initiation and/or Modulation?.Cancers (Basel). 2019 Feb 21;11(2):252. doi: 10.3390/cancers11020252.
2	GDF-15 and TRAIL-R2 are powerful predictors of long-term mortality in patients with acute myocardial infarction.Eur J Prev Cardiol. 2017 Oct;24(15):1576-1583. doi: 10.1177/2047487317725017. Epub 2017 Aug 1.
3	Specificity for latent C termini links the E3 ubiquitin ligase CHIP to caspases.Nat Chem Biol. 2019 Aug;15(8):786-794. doi: 10.1038/s41589-019-0322-6. Epub 2019 Jul 18.
4	Neuropathy-causing mutations in HSPB1 impair autophagy by disturbing the formation of SQSTM1/p62 bodies.Autophagy. 2019 Jun;15(6):1051-1068. doi: 10.1080/15548627.2019.1569930. Epub 2019 Jan 31.
5	Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure.JAMA Cardiol. 2019 Jan 1;4(1):25-33. doi: 10.1001/jamacardio.2018.3965.
6	Estimating minimal important differences for several scales assessing function and quality of life in patients with attention-deficit/hyperactivity disorder.CNS Spectr. 2017 Feb;22(1):31-40. doi: 10.1017/S1092852916000353. Epub 2016 Aug 18.
7	Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
8	Post-translational modification of OCT4 in breast cancer tumorigenesis.Cell Death Differ. 2018 Nov;25(10):1781-1795. doi: 10.1038/s41418-018-0079-6. Epub 2018 Mar 6.
9	Cerebellar cognitive-affective syndrome preceding ataxia associated with complex extrapyramidal features in a Turkish SCA48 family.Neurogenetics. 2020 Jan;21(1):51-58. doi: 10.1007/s10048-019-00595-0. Epub 2019 Nov 19.
10	Establishment of STUB1/CHIP mutant induced pluripotent stem cells (iPSCs) from a patient with Gordon Holmes syndrome/SCAR16.Stem Cell Res. 2018 May;29:166-169. doi: 10.1016/j.scr.2018.04.001. Epub 2018 Apr 9.
11	Targeting STUB1-tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk.Sci Transl Med. 2017 Nov 22;9(417):eaam8475. doi: 10.1126/scitranslmed.aam8475.
12	CHIP/Stub1 functions as a tumor suppressor and represses NF-B-mediated signaling in colorectal cancer.Carcinogenesis. 2014 May;35(5):983-91. doi: 10.1093/carcin/bgt393. Epub 2013 Dec 3.
13	Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway.Int J Cancer. 2019 Oct 1;145(7):1921-1934. doi: 10.1002/ijc.32293. Epub 2019 Apr 4.
14	Cancer stem-like cell related protein CD166 degrades through E3 ubiquitin ligase CHIP in head and neck cancer.Exp Cell Res. 2017 Apr 1;353(1):46-53. doi: 10.1016/j.yexcr.2017.03.005. Epub 2017 Mar 6.
15	STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations.Orphanet J Rare Dis. 2017 Feb 13;12(1):31. doi: 10.1186/s13023-017-0580-x.
16	The E3 Ligase CHIP Mediates p21 Degradation to Maintain Radioresistance.Mol Cancer Res. 2017 Jun;15(6):651-659. doi: 10.1158/1541-7786.MCR-16-0466. Epub 2017 Feb 23.
17	An inflammatory environment containing TNF favors Tet2-mutant clonal hematopoiesis.Exp Hematol. 2018 Mar;59:60-65. doi: 10.1016/j.exphem.2017.11.002. Epub 2017 Nov 28.
18	The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families.Eur J Neurol. 2020 Mar;27(3):498-505. doi: 10.1111/ene.14094. Epub 2019 Nov 1.
19	ICUS, IDUS, CHIP and CCUS: Diagnostic Criteria, Separation from MDS and Clinical Implications.Pathobiology. 2019;86(1):30-38. doi: 10.1159/000489042. Epub 2018 Jun 1.
20	Multifaceted C-terminus of HSP70-interacting protein regulates tumorigenesis via protein quality control.Arch Pharm Res. 2019 Jan;42(1):63-75. doi: 10.1007/s12272-018-1101-8. Epub 2019 Jan 1.
21	Protocol: investigating the effectiveness and cost benefit of a lifestyle intervention targeting type 2 diabetes in Australia.BMC Endocr Disord. 2019 Jul 15;19(1):74. doi: 10.1186/s12902-019-0396-x.
22	CHIP/Stub1 regulates the Warburg effect by promoting degradation of PKM2 in ovarian carcinoma.Oncogene. 2017 Jul 20;36(29):4191-4200. doi: 10.1038/onc.2017.31. Epub 2017 Mar 27.
23	The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF.Oncogene. 2010 Oct 21;29(42):5667-77. doi: 10.1038/onc.2010.327. Epub 2010 Aug 9.
24	Association study of androgen signaling pathway genes in polycystic ovary syndrome.Fertil Steril. 2016 Feb;105(2):467-73.e4. doi: 10.1016/j.fertnstert.2015.09.043. Epub 2015 Oct 20.
25	Mutations associated with age-related clonal hematopoiesis in PMF patients with rapid progression to myelofibrosis.Leukemia. 2020 May;34(5):1364-1372. doi: 10.1038/s41375-019-0668-5. Epub 2019 Nov 27.
26	Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer.Nat Commun. 2018 Nov 16;9(1):4700. doi: 10.1038/s41467-018-07178-x.
27	Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
28	Molecular heterogeneity in chronic lymphocytic leukemia is dependent on BCR signaling: clinical correlation.Leukemia. 2007 Sep;21(9):1984-91. doi: 10.1038/sj.leu.2404831. Epub 2007 Jul 5.
29	Transcription factor RFX1 is ubiquitinated by E3 ligase STUB1 in systemic lupus erythematosus.Clin Immunol. 2016 Aug;169:1-7. doi: 10.1016/j.clim.2016.06.003. Epub 2016 Jun 6.
30	The ubiquitin ligase STUB1 regulates stability and activity of RUNX1 and RUNX1-RUNX1T1.J Biol Chem. 2017 Jul 28;292(30):12528-12541. doi: 10.1074/jbc.M117.785675. Epub 2017 May 23.
31	GSK3 controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug.Oncogene. 2017 Oct 19;36(42):5916. doi: 10.1038/onc.2017.302. Epub 2017 Sep 4.
32	The mechanism of SP1/p300 complex promotes proliferation of multiple myeloma cells through regulating IQGAP1 transcription.Biomed Pharmacother. 2019 Nov;119:109434. doi: 10.1016/j.biopha.2019.109434. Epub 2019 Sep 16.
33	The ubiquitin ligase CHIP modulates cellular behaviors of gastric cancer cells by regulating TRAF2.Cancer Cell Int. 2019 May 16;19:132. doi: 10.1186/s12935-019-0832-z. eCollection 2019.
34	STUB1 suppresseses tumorigenesis and chemoresistance through antagonizing YAP1 signaling.Cancer Sci. 2019 Oct;110(10):3145-3156. doi: 10.1111/cas.14166. Epub 2019 Aug 28.
35	CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity.Mol Cell. 2002 Jul;10(1):55-67. doi: 10.1016/s1097-2765(02)00583-x.
36	MicroRNA-663 suppresses cell invasion and migration by targeting transforming growth factor beta 1 in papillary thyroid carcinoma.Tumour Biol. 2016 Jun;37(6):7633-44. doi: 10.1007/s13277-015-4653-y. Epub 2015 Dec 19.
37	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.
38	Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
39	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
40	Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
41	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.
42	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.
43	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.