Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT58AP1I)

• DOT Name: Krev interaction trapped protein 1 (KRIT1)
• Synonyms: Krev interaction trapped 1; Cerebral cavernous malformations 1 protein
• Gene Name: KRIT1
• Related Disease:
  Adult glioblastoma
  Cerebral cavernous malformation 1
  Glioblastoma multiforme
  Adenocarcinoma
  Alzheimer disease
  Arrhythmia
  Arteriosclerosis
  Atherosclerosis
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Cerebral cavernous malformation 2
  Cerebral cavernous malformation 3
  Cerebrovascular disease
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Delirium
  Epithelial ovarian cancer
  Gastric cancer
  Meningioma
  Metastatic malignant neoplasm
  Multiple sclerosis
  Non-hodgkin lymphoma
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Rheumatoid arthritis
  Schizophrenia
  Small-cell lung cancer
  Stomach cancer
  Systemic lupus erythematosus
  Urinary bladder cancer
  Urinary bladder neoplasm
  X-linked hydrocephalus with stenosis of the aqueduct of Sylvius
  Vascular malformation
  Famililal cerebral cavernous malformations
  Advanced cancer
  Arthritis
  Glioma
  Hepatitis C virus infection
  Lymphoma, non-Hodgkin, familial
  Neuroblastoma
  Renal carcinoma
• UniProt ID: KRIT1_HUMAN
• PDB ID: 3U7D; 4DX8; 4DXA; 4HDO; 4HDQ; 4JIF; 4TKN; 5D68; 6OQ3; 6OQ4; 6UZK; 8SU8; 8T7V
• Pfam ID: PF13857 ; PF00373 ; PF16705
• Sequence:
  MGNPENIEDAYVAVIRPKNTASLNSREYRAKSYEILLHEVPIEGQKKKRKKVLLETKLQG
  NSEITQGILDYVVETTKPISPANQGIRGKRVVLMKKFPLDGEKMGREASLFIVPSVVKDN
  TKYTYTPGCPIFYCLQDIMRVCSESSTHFATLTARMLIALDKWLDERHAQSHFIPALFRP
  SPLERIKTNVINPAYATESGQTENSLHMGYSALEIKSKMLALEKADTCIYNPLFGSDLQY
  TNRVDKVVINPYFGLGAPDYSKIQIPKQEKWQRSMSSVTEDKERQWVDDFPLHRSACEGD
  SELLSRLLSERFSVNQLDSDHWAPIHYACWYGKVEATRILLEKGKCNPNLLNGQLSSPLH
  FAAGGGHAEIVQILLNHPETDRHITDQQGRSPLNICEENKQNNWEEAAKLLKEAINKPYE
  KVRIYRMDGSYRSVELKHGNNTTVQQIMEGMRLSQETQQYFTIWICSENLSLQLKPYHKP
  LQHVRDWPEILAELTNLDPQRETPQLFLRRDVRLPLEVEKQIEDPLAILILFDEARYNLL
  KGFYTAPDAKLITLASLLLQIVYGNYESKKHKQGFLNEENLKSIVPVTKLKSKAPHWTNR
  ILHEYKNLSTSEGVSKEMHHLQRMFLQNCWEIPTYGAAFFTGQIFTKASPSNHKVIPVYV
  GVNIKGLHLLNMETKALLISLKYGCFMWQLGDTDTCFQIHSMENKMSFIVHTKQAGLVVK
  LLMKLNGQLMPTERNS
• Function: Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity. Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits ERK1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establish and maintain correct endothelial cell polarity and vascular lumen and these effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction, and cell junction stabilization. Plays a role in integrin signaling via its interaction with ITGB1BP1; this prevents the interaction between ITGB1 and ITGB1BP1. Microtubule-associated protein that binds to phosphatidylinositol 4,5-bisphosphate (PIP2)-containing membranes in a GTP-bound RAP1-dependent manner. Plays an important role in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage. Regulates the homeostasis of intracellular ROS through an antioxidant pathway involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1 (CCND1) levels required for cell transition from proliferative growth to quiescence by preventing the accumulation of intracellular ROS through the modulation of FOXO1 and SOD2 levels. May play a role in the regulation of macroautophagy through the down-regulation of the mTOR pathway.
• Tissue Specificity: Low levels in brain. Very weak expression found in heart and muscle.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Adherens junction (hsa04520)
• BioCyc Pathway: MetaCyc:ENSG00000001631-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Cerebral cavernous malformation 1	DIST5TVM	Definitive	Autosomal dominant	[2]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Arrhythmia	DISFF2NI	Strong	Genetic Variation	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Bladder cancer	DISUHNM0	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[9]
Carcinoma	DISH9F1N	Strong	Biomarker	[8]
Cerebral cavernous malformation 2	DIS7DG9B	Strong	Genetic Variation	[10]
Cerebral cavernous malformation 3	DISHAV0P	Strong	Genetic Variation	[10]
Cerebrovascular disease	DISAB237	Strong	Genetic Variation	[11]
Colon cancer	DISVC52G	Strong	Biomarker	[12]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Delirium	DIS2OKP1	Strong	Biomarker	[13]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[14]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[15]
Meningioma	DISPT4TG	Strong	Altered Expression	[16]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[3]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[17]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[18]
Obesity	DIS47Y1K	Strong	Genetic Variation	[19]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[14]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[14]
Prostate cancer	DISF190Y	Strong	Biomarker	[20]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[20]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[21]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[22]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[23]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[24]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[15]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[22]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[7]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[7]
X-linked hydrocephalus with stenosis of the aqueduct of Sylvius	DIS6QXIR	Strong	Genetic Variation	[25]
Vascular malformation	DIS2DB7A	moderate	Genetic Variation	[26]
Famililal cerebral cavernous malformations	DISP72I1	Supportive	Autosomal dominant	[27]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[28]
Arthritis	DIST1YEL	Limited	Biomarker	[29]
Glioma	DIS5RPEH	Limited	Biomarker	[30]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[31]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Limited	Biomarker	[18]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[32]
Renal carcinoma	DISER9XT	Limited	Biomarker	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Krev interaction trapped protein 1 (KRIT1).	[34]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Krev interaction trapped protein 1 (KRIT1).	[35]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Krev interaction trapped protein 1 (KRIT1).	[36]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Krev interaction trapped protein 1 (KRIT1).	[37]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Krev interaction trapped protein 1 (KRIT1).	[38]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Krev interaction trapped protein 1 (KRIT1).	[39]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Krev interaction trapped protein 1 (KRIT1).	[40]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Krev interaction trapped protein 1 (KRIT1).	[41]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Krev interaction trapped protein 1 (KRIT1).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Krev interaction trapped protein 1 (KRIT1).	[43]
Taurine	DMVW7N3	Investigative	Taurine increases the expression of Krev interaction trapped protein 1 (KRIT1).	[44]

References

• [1] Riluzole: a potential therapeutic intervention in human brain tumor stem-like cells.Oncotarget. 2017 May 20;8(57):96697-96709. doi: 10.18632/oncotarget.18043. eCollection 2017 Nov 14.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] L-CAM expression in lymph node and liver metastases of colorectal carcinomas.J Pathol. 1994 Feb;172(2):177-81. doi: 10.1002/path.1711720204.
• [4] Modulating Conformation of A-Peptide: An Effective Way to Prevent Protein-Misfolding Disease.Inorg Chem. 2018 Nov 5;57(21):13533-13543. doi: 10.1021/acs.inorgchem.8b02115. Epub 2018 Oct 22.
• [5] Protein phenotype diagnosis of autosomal dominant calmodulin mutations causing irregular heart rhythms.J Cell Biochem. 2018 Nov;119(10):8233-8248. doi: 10.1002/jcb.26834. Epub 2018 Jun 22.
• [6] KRIT1 Deficiency Promotes Aortic Endothelial Dysfunction.Int J Mol Sci. 2019 Oct 5;20(19):4930. doi: 10.3390/ijms20194930.
• [7] Suppression of human bladder cancer growth by increased expression of C-CAM1 gene in an orthotopic model.Cancer Res. 1996 Aug 1;56(15):3431-5.
• [8] Expression and prognostic value of L1-CAM in breast cancer.Oncol Rep. 2009 Nov;22(5):1109-17. doi: 10.3892/or_00000543.
• [9] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [10] Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review.JAMA Neurol. 2019 Apr 1;76(4):492-500. doi: 10.1001/jamaneurol.2018.3634.
• [11] KRIT1 Loss-Of-Function Associated with Cerebral Cavernous Malformation Disease Leads to Enhanced S-Glutathionylation of Distinct Structural and Regulatory Proteins.Antioxidants (Basel). 2019 Jan 17;8(1):27. doi: 10.3390/antiox8010027.
• [12] Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis.Cancer Res. 2007 Aug 15;67(16):7703-12. doi: 10.1158/0008-5472.CAN-07-0991.
• [13] Protocol for a prospective cohort study of assessing postoperative cognitive changes after total hip and knee arthroplasty in the Greater Toronto area.BMJ Open. 2019 Feb 24;9(2):e024259. doi: 10.1136/bmjopen-2018-024259.
• [14] L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice.PLoS One. 2016 Jan 13;11(1):e0146885. doi: 10.1371/journal.pone.0146885. eCollection 2016.
• [15] Clinical Application of the DiversiLab Microbial Typing System Using Repetitive Sequence-Based PCR for Characterization of Helicobacter pylori in Japan.J Clin Lab Anal. 2015 May;29(3):250-3. doi: 10.1002/jcla.21758. Epub 2014 May 5.
• [16] Anaplastic meningioma versus meningeal hemangiopericytoma: immunohistochemical and genetic markers.Hum Pathol. 2004 Nov;35(11):1413-8. doi: 10.1016/j.humpath.2004.07.017.
• [17] A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility.Genes Immun. 2014 Mar;15(2):126-32. doi: 10.1038/gene.2013.70. Epub 2014 Jan 16.
• [18] Upregulation of ADAM12 contributes to accelerated cell proliferation and cell adhesion-mediated drug resistance (CAM-DR) in Non-Hodgkin's Lymphoma.Hematology. 2017 Oct;22(9):527-535. doi: 10.1080/10245332.2017.1312205. Epub 2017 Apr 10.
• [19] Association of cardiovascular risk factors with disease severity in cerebral cavernous malformation type 1 subjects with the common Hispanic mutation.Cerebrovasc Dis. 2014;37(1):57-63. doi: 10.1159/000356839. Epub 2013 Dec 21.
• [20] Function and therapeutic implication of C-CAM cell-adhesion molecule in prostate cancer.Semin Oncol. 1999 Apr;26(2):227-33.
• [21] Anti-neuroblastoma antibody chCE7 binds to an isoform of L1-CAM present in renal carcinoma cells.Int J Cancer. 1999 Oct 29;83(3):401-8. doi: 10.1002/(sici)1097-0215(19991029)83:3<401::aid-ijc17>3.0.co;2-a.
• [22] Influence of treatments on cell adhesion molecules in patients with systemic lupus erythematosus and rheumatoid arthritis: a review.Inflammopharmacology. 2020 Apr;28(2):363-384. doi: 10.1007/s10787-019-00674-6. Epub 2019 Dec 9.
• [23] Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility.Mol Psychiatry. 2011 Mar;16(3):286-92. doi: 10.1038/mp.2010.7. Epub 2010 Feb 16.
• [24] Capsaicin displays anti-proliferative activity against human small cell lung cancer in cell culture and nude mice models via the E2F pathway.PLoS One. 2010 Apr 20;5(4):e10243. doi: 10.1371/journal.pone.0010243.
• [25] Nine novel L1 CAM mutations in families with X-linked hydrocephalus.Hum Mutat. 1997;9(6):512-8. doi: 10.1002/(SICI)1098-1004(1997)9:6<512::AID-HUMU3>3.0.CO;2-3.
• [26] A Novel KRIT1/CCM1 Gene Insertion Mutation Associated with Cerebral Cavernous Malformations in a Chinese Family.J Mol Neurosci. 2017 Feb;61(2):221-226. doi: 10.1007/s12031-017-0881-5. Epub 2017 Feb 3.
• [27] Familial Cerebral Cavernous Malformations. 2003 Feb 24 [updated 2023 Jul 27]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [28] Cancer Biomarkers for Integrative Oncology.Curr Oncol Rep. 2019 Mar 5;21(4):32. doi: 10.1007/s11912-019-0782-6.
• [29] Movement and manual therapy for adults with arthritis: 2012 National Health Interview Survey.Complement Ther Med. 2018 Apr;37:96-102. doi: 10.1016/j.ctim.2018.02.007. Epub 2018 Mar 2.
• [30] CD155/PVR enhances glioma cell dispersal by regulating adhesion signaling and focal adhesion dynamics.Cancer Res. 2005 Dec 1;65(23):10930-7. doi: 10.1158/0008-5472.CAN-05-1890.
• [31] Comparison of conventional PCR with real-time PCR and branched DNA-based assays for hepatitis C virus RNA quantification and clinical significance for genotypes 1 to 5.J Clin Microbiol. 2006 Mar;44(3):729-37. doi: 10.1128/JCM.44.3.729-737.2006.
• [32] SPARC overexpression combined with radiation retards angiogenesis by suppressing VEGF-A via miR?10 in human neuroblastoma cells.Int J Oncol. 2016 Oct;49(4):1394-406. doi: 10.3892/ijo.2016.3646. Epub 2016 Aug 3.
• [33] The transcription factor PAX2 regulates ADAM10 expression in renal cell carcinoma.Carcinogenesis. 2011 Nov;32(11):1713-23. doi: 10.1093/carcin/bgr195. Epub 2011 Aug 30.
• [34] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [35] 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.
• [36] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [37] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [38] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [39] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [40] 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.
• [41] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [42] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [43] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [44] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.