Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9ZJX1I)

DOT Name Calcium and integrin-binding family member 2 (CIB2)
Synonyms Kinase-interacting protein 2; KIP 2
Gene Name CIB2
Related Disease
Autosomal recessive nonsyndromic hearing loss 48 ( )
Nonsyndromic genetic hearing loss ( )
Usher syndrome type 1J ( )
Wilms tumor ( )
Acute lymphocytic leukaemia ( )
Adenoma ( )
Asthma ( )
B-cell lymphoma ( )
Bladder cancer ( )
Breast cancer ( )
Breast carcinoma ( )
Breast neoplasm ( )
Childhood myelodysplastic syndrome ( )
Choriocarcinoma ( )
Chronic obstructive pulmonary disease ( )
Colorectal carcinoma ( )
Complete hydatidiform mole ( )
Deafness ( )
Epithelial ovarian cancer ( )
Hepatocellular carcinoma ( )
Hydatidiform mole ( )
Hydatidiform mole, recurrent, 1 ( )
Hyperinsulinemia ( )
IgA nephropathy ( )
Lung cancer ( )
Lung carcinoma ( )
Myelodysplastic syndrome ( )
Non-small-cell lung cancer ( )
Ovarian cancer ( )
Ovarian neoplasm ( )
Squamous cell carcinoma ( )
Tarsal-carpal coalition syndrome ( )
Type-1/2 diabetes ( )
Urinary bladder cancer ( )
Urinary bladder neoplasm ( )
Malignant soft tissue neoplasm ( )
Nasopharyngeal carcinoma ( )
Sarcoma ( )
Soft tissue sarcoma ( )
Hearing loss, autosomal recessive ( )
Usher syndrome type 1 ( )
Advanced cancer ( )
Beckwith-Wiedemann syndrome ( )
Childhood kidney Wilms tumor ( )
Gallbladder cancer ( )
Gallbladder carcinoma ( )
Gonorrhea ( )
Laryngeal squamous cell carcinoma ( )
Schizophrenia ( )
Usher syndrome ( )
UniProt ID
CIB2_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
Pfam ID
PF13499
Sequence
MGNKQTIFTEEQLDNYQDCTFFNKKDILKLHSRFYELAPNLVPMDYRKSPIVHVPMSLII
QMPELRENPFKERIVAAFSEDGEGNLTFNDFVDMFSVLCESAPRELKANYAFKIYDFNTD
NFICKEDLELTLARLTKSELDEEEVVLVCDKVIEEADLDGDGKLGFADFEDMIAKAPDFL
STFHIRI
Function
Calcium- and integrin-binding protein that plays a role in intracellular calcium homeostasis. Acts as an auxiliary subunit of the sensory mechanoelectrical transduction (MET) channel in hair cells. Essential for mechanoelectrical transduction (MET) currents in auditory hair cells and thereby required for hearing. Regulates the function of hair cell mechanotransduction by controlling the distribution of transmembrane channel-like proteins TMC1 and TMC2, and by regulating the function of the MET channels in hair cells. Required for the maintenance of auditory hair cell stereocilia bundle morphology and function and for hair-cell survival in the cochlea. Critical for proper photoreceptor cell maintenance and function. Plays a role in intracellular calcium homeostasis by decreasing ATP-induced calcium release.
Tissue Specificity Widely expressed .
Reactome Pathway
Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361 )
Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360 )

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Autosomal recessive nonsyndromic hearing loss 48 DIS5WCEY Definitive Autosomal recessive [1]
Nonsyndromic genetic hearing loss DISZX61P Definitive Autosomal recessive [2]
Usher syndrome type 1J DISL6IZ6 Definitive Autosomal recessive [3]
Wilms tumor DISB6T16 Definitive Biomarker [4]
Acute lymphocytic leukaemia DISPX75S Strong Biomarker [5]
Adenoma DIS78ZEV Strong Genetic Variation [6]
Asthma DISW9QNS Strong Biomarker [7]
B-cell lymphoma DISIH1YQ Strong Posttranslational Modification [8]
Bladder cancer DISUHNM0 Strong Posttranslational Modification [9]
Breast cancer DIS7DPX1 Strong Altered Expression [10]
Breast carcinoma DIS2UE88 Strong Altered Expression [10]
Breast neoplasm DISNGJLM Strong Biomarker [11]
Childhood myelodysplastic syndrome DISMN80I Strong Genetic Variation [8]
Choriocarcinoma DISDBVNL Strong Genetic Variation [12]
Chronic obstructive pulmonary disease DISQCIRF Strong Biomarker [7]
Colorectal carcinoma DIS5PYL0 Strong Altered Expression [13]
Complete hydatidiform mole DIS5QPI0 Strong Genetic Variation [14]
Deafness DISKCLH4 Strong Genetic Variation [15]
Epithelial ovarian cancer DIS56MH2 Strong Biomarker [16]
Hepatocellular carcinoma DIS0J828 Strong Biomarker [17]
Hydatidiform mole DISKNP7O Strong Altered Expression [18]
Hydatidiform mole, recurrent, 1 DISXUJWE Strong Altered Expression [18]
Hyperinsulinemia DISIDWT6 Strong Genetic Variation [19]
IgA nephropathy DISZ8MTK Strong Altered Expression [20]
Lung cancer DISCM4YA Strong Altered Expression [21]
Lung carcinoma DISTR26C Strong Altered Expression [21]
Myelodysplastic syndrome DISYHNUI Strong Genetic Variation [8]
Non-small-cell lung cancer DIS5Y6R9 Strong Altered Expression [22]
Ovarian cancer DISZJHAP Strong Biomarker [16]
Ovarian neoplasm DISEAFTY Strong Biomarker [16]
Squamous cell carcinoma DISQVIFL Strong Altered Expression [23]
Tarsal-carpal coalition syndrome DISY90L2 Strong Altered Expression [24]
Type-1/2 diabetes DISIUHAP Strong Altered Expression [25]
Urinary bladder cancer DISDV4T7 Strong Posttranslational Modification [9]
Urinary bladder neoplasm DIS7HACE Strong Posttranslational Modification [9]
Malignant soft tissue neoplasm DISTC6NO moderate Genetic Variation [26]
Nasopharyngeal carcinoma DISAOTQ0 moderate Biomarker [27]
Sarcoma DISZDG3U moderate Genetic Variation [26]
Soft tissue sarcoma DISSN8XB moderate Genetic Variation [26]
Hearing loss, autosomal recessive DIS8G9R9 Supportive Autosomal recessive [1]
Usher syndrome type 1 DISR29E4 Supportive Autosomal recessive [1]
Advanced cancer DISAT1Z9 Limited Biomarker [16]
Beckwith-Wiedemann syndrome DISH15GR Limited Biomarker [28]
Childhood kidney Wilms tumor DIS0NMK3 Limited Altered Expression [29]
Gallbladder cancer DISXJUAF Limited Biomarker [30]
Gallbladder carcinoma DISD6ACL Limited Biomarker [30]
Gonorrhea DISQ5AO6 Limited Biomarker [30]
Laryngeal squamous cell carcinoma DIS9UUVF Limited Biomarker [31]
Schizophrenia DISSRV2N Limited Biomarker [32]
Usher syndrome DIS9YIS7 Limited Biomarker [33]
------------------------------------------------------------------------------------
⏷ Show the Full List of 50 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
5 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of Calcium and integrin-binding family member 2 (CIB2). [34]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Calcium and integrin-binding family member 2 (CIB2). [35]
Arsenic DMTL2Y1 Approved Arsenic increases the expression of Calcium and integrin-binding family member 2 (CIB2). [36]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Calcium and integrin-binding family member 2 (CIB2). [37]
Tocopherol DMBIJZ6 Phase 2 Tocopherol increases the expression of Calcium and integrin-binding family member 2 (CIB2). [38]
------------------------------------------------------------------------------------
1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Calcium and integrin-binding family member 2 (CIB2). [39]
------------------------------------------------------------------------------------

References

1 Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. Nat Genet. 2012 Nov;44(11):1265-71. doi: 10.1038/ng.2426. Epub 2012 Sep 30.
2 Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
3 USH1H, a novel locus for type I Usher syndrome, maps to chromosome 15q22-23. Clin Genet. 2009 Jan;75(1):86-91. doi: 10.1111/j.1399-0004.2008.01038.x. Epub 2008 May 25.
4 Human p57(KIP2) defines a new imprinted domain on chromosome 11p but is not a tumour suppressor gene in Wilms tumour.Oncogene. 1997 Mar 13;14(10):1201-6. doi: 10.1038/sj.onc.1200934.
5 Residual DNA methylation at remission is prognostic in adult Philadelphia chromosome-negative acute lymphocytic leukemia.Blood. 2009 Feb 26;113(9):1892-8. doi: 10.1182/blood-2008-02-141002. Epub 2008 Dec 23.
6 Uncontrolled insulin secretion from a childhood pancreatic beta-cell adenoma is not due to the functional loss of ATP-sensitive potassium channels.Endocr Relat Cancer. 2002 Dec;9(4):221-6. doi: 10.1677/erc.0.0090221.
7 Inflammatory stimuli inhibit glucocorticoid-dependent transactivation in human pulmonary epithelial cells: rescue by long-acting beta2-adrenoceptor agonists.J Pharmacol Exp Ther. 2011 Sep;338(3):860-9. doi: 10.1124/jpet.111.181016. Epub 2011 May 27.
8 Aberrant DNA methylation of p57(KIP2) gene in the promoter region in lymphoid malignancies of B-cell phenotype.Blood. 2002 Oct 1;100(7):2572-7. doi: 10.1182/blood-2001-11-0026.
9 Decreased expression of p57(KIP2)mRNA in human bladder cancer.Br J Cancer. 2000 Sep;83(5):626-31. doi: 10.1054/bjoc.2000.1298.
10 The KIP/CIP family members p21^{Waf1/Cip1} and p57^{Kip2} as diagnostic markers for breast cancer.Cancer Biomark. 2017;18(4):413-423. doi: 10.3233/CBM-160308.
11 CDK inhibitor p57 (Kip2) is downregulated by Akt during HER2-mediated tumorigenicity.Cell Cycle. 2013 Mar 15;12(6):935-43. doi: 10.4161/cc.23883. Epub 2013 Feb 19.
12 Gestational choriocarcinoma of Fallopian tube diagnosed with a combination of p57KIP2 immunostaining and short tandem repeat analysis: case report.J Obstet Gynaecol Res. 2011 Oct;37(10):1493-6. doi: 10.1111/j.1447-0756.2011.01538.x. Epub 2011 May 22.
13 Hsa-miR-875-5p exerts tumor suppressor function through down-regulation of EGFR in colorectal carcinoma (CRC).Oncotarget. 2016 Jul 5;7(27):42225-42240. doi: 10.18632/oncotarget.9944.
14 Clinical Usefulness of Immunohistochemical Staining of p57 kip2 for the Differential Diagnosis of Complete Mole.Biomed Res Int. 2015;2015:905648. doi: 10.1155/2015/905648. Epub 2015 Jun 16.
15 Genetics of Usher Syndrome: New Insights From a Meta-analysis.Otol Neurotol. 2019 Jan;40(1):121-129. doi: 10.1097/MAO.0000000000002054.
16 CIB2 Negatively Regulates Oncogenic Signaling in Ovarian Cancer via Sphingosine Kinase 1.Cancer Res. 2017 Sep 15;77(18):4823-4834. doi: 10.1158/0008-5472.CAN-17-0025. Epub 2017 Jul 20.
17 The degradation of cell cycle regulators by SKP2/CKS1 ubiquitin ligase is genetically controlled in rodent liver cancer and contributes to determine the susceptibility to the disease.Int J Cancer. 2010 Mar 1;126(5):1275-81. doi: 10.1002/ijc.24650.
18 Abnormal villous morphology mimicking a hydatidiform mole associated with paternal trisomy of chromosomes 3,7,8 and unipaternal disomy of chromosome 11.Diagn Pathol. 2016 Feb 4;11:20. doi: 10.1186/s13000-016-0471-9.
19 Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism.Mod Pathol. 2006 Jan;19(1):122-9. doi: 10.1038/modpathol.3800497.
20 Downregulation of Bcl-2 by podocytes is associated with progressive glomerular injury and clinical indices of poor renal prognosis in human IgA nephropathy.J Am Soc Nephrol. 2004 Jan;15(1):79-90. doi: 10.1097/01.asn.0000104573.54132.2e.
21 Decreased expression of decorin and p57(KIP2) correlates with poor survival and lymphatic metastasis in lung cancer patients.Int J Biol Markers. 2011 Jan-Mar;26(1):9-21. doi: 10.5301/jbm.2011.6372.
22 Hsa-miR-326 targets CCND1 and inhibits non-small cell lung cancer development.Oncotarget. 2016 Feb 16;7(7):8341-59. doi: 10.18632/oncotarget.7071.
23 High expression of S-phase kinase-interacting protein 2, human F-box protein, correlates with poor prognosis in oral squamous cell carcinomas. Cancer Res. 2001 Oct 1;61(19):7044-7.
24 Multiple mechanisms downregulate CDKN1C in human bladder cancer.Int J Cancer. 2005 Apr 10;114(3):406-13. doi: 10.1002/ijc.20749.
25 p57(KIP2) expression in normal islet cells and in hyperinsulinism of infancy. Diabetes. 2001 Dec;50(12):2763-9.
26 Cyclin-dependent kinase inhibitor p57KIP2 in soft tissue sarcomas and Wilms'tumors.Cancer Res. 1996 Mar 15;56(6):1219-21.
27 Downregulation of p57kip promotes cell invasion via LIMK/cofilin pathway in human nasopharyngeal carcinoma cells.J Cell Biochem. 2011 Nov;112(11):3459-68. doi: 10.1002/jcb.23277.
28 p57(Kip2) knock-in mouse reveals CDK-independent contribution in the development of Beckwith-Wiedemann syndrome.J Pathol. 2016 Jul;239(3):250-61. doi: 10.1002/path.4721. Epub 2016 May 4.
29 Coding mutations in p57KIP2 are present in some cases of Beckwith-Wiedemann syndrome but are rare or absent in Wilms tumors.Am J Hum Genet. 1997 Aug;61(2):295-303. doi: 10.1086/514854.
30 Expression of p21(Wafl/Cip1), p57(Kip2) and HER2/neu in patients with gallbladder cancer.Anticancer Res. 2007 May-Jun;27(3B):1679-84.
31 p57(kip2) expression is related to carcinogenesis and tumor progression in laryngeal tissues.Acta Otolaryngol. 2006 Mar;126(3):301-5. doi: 10.1080/00016480500388851.
32 Abnormal indices of cell cycle activity in schizophrenia and their potential association with oligodendrocytes.Neuropsychopharmacology. 2008 Nov;33(12):2993-3009. doi: 10.1038/npp.2008.19. Epub 2008 Mar 5.
33 Variants in CIB2 cause DFNB48 and not USH1J.Clin Genet. 2018 Apr;93(4):812-821. doi: 10.1111/cge.13170. Epub 2018 Feb 12.
34 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
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 Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
37 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
38 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.
39 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.