Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6W5BNR)

• DOT Name: Clathrin heavy chain 2 (CLTCL1)
• Synonyms: Clathrin heavy chain on chromosome 22; CLH-22
• Gene Name: CLTCL1
• Related Disease:
  Anaplastic large cell lymphoma
  Meningioma
  Neoplasm
  Rhabdomyosarcoma
  Congenital insensitivity to pain with severe intellectual disability
  Multiple congenital anomalies/dysmorphic syndrome
• UniProt ID: CLH2_HUMAN
• Pfam ID: PF00637 ; PF09268 ; PF13838 ; PF01394
• Sequence:
  MAQILPVRFQEHFQLQNLGINPANIGFSTLTMESDKFICIREKVGEQAQVTIIDMSDPMA
  PIRRPISAESAIMNPASKVIALKAGKTLQIFNIEMKSKMKAHTMAEEVIFWKWVSVNTVA
  LVTETAVYHWSMEGDSQPMKMFDRHTSLVGCQVIHYRTDEYQKWLLLVGISAQQNRVVGA
  MQLYSVDRKVSQPIEGHAAAFAEFKMEGNAKPATLFCFAVRNPTGGKLHIIEVGQPAAGN
  QPFVKKAVDVFFPPEAQNDFPVAMQIGAKHGVIYLITKYGYLHLYDLESGVCICMNRISA
  DTIFVTAPHKPTSGIIGVNKKGQVLSVCVEEDNIVNYATNVLQNPDLGLRLAVRSNLAGA
  EKLFVRKFNTLFAQGSYAEAAKVAASAPKGILRTRETVQKFQSIPAQSGQASPLLQYFGI
  LLDQGQLNKLESLELCHLVLQQGRKQLLEKWLKEDKLECSEELGDLVKTTDPMLALSVYL
  RANVPSKVIQCFAETGQFQKIVLYAKKVGYTPDWIFLLRGVMKISPEQGLQFSRMLVQDE
  EPLANISQIVDIFMENSLIQQCTSFLLDALKNNRPAEGLLQTWLLEMNLVHAPQVADAIL
  GNKMFTHYDRAHIAQLCEKAGLLQQALEHYTDLYDIKRAVVHTHLLNPEWLVNFFGSLSV
  EDSVECLHAMLSANIRQNLQLCVQVASKYHEQLGTQALVELFESFKSYKGLFYFLGSIVN
  FSQDPDVHLKYIQAACKTGQIKEVERICRESSCYNPERVKNFLKEAKLTDQLPLIIVCDR
  FGFVHDLVLYLYRNNLQRYIEIYVQKVNPSRTPAVIGGLLDVDCSEEVIKHLIMAVRGQF
  STDELVAEVEKRNRLKLLLPWLESQIQEGCEEPATHNALAKIYIDSNNSPECFLRENAYY
  DSSVVGRYCEKRDPHLACVAYERGQCDLELIKVCNENSLFKSEARYLVCRKDPELWAHVL
  EETNPSRRQLIDQVVQTALSETRDPEEISVTVKAFMTADLPNELIELLEKIVLDNSVFSE
  HRNLQNLLILTAIKADRTRVMEYISRLDNYDALDIASIAVSSALYEEAFTVFHKFDMNAS
  AIQVLIEHIGNLDRAYEFAERCNEPAVWSQLAQAQLQKDLVKEAINSYIRGDDPSSYLEV
  VQSASRSNNWEDLVKFLQMARKKGRESYIETELIFALAKTSRVSELEDFINGPNNAHIQQ
  VGDRCYEEGMYEAAKLLYSNVSNFARLASTLVHLGEYQAAVDNSRKASSTRTWKEVCFAC
  MDGQEFRFAQLCGLHIVIHADELEELMCYYQDRGYFEELILLLEAALGLERAHMGMFTEL
  AILYSKFKPQKMLEHLELFWSRVNIPKVLRAAEQAHLWAELVFLYDKYEEYDNAVLTMMS
  HPTEAWKEGQFKDIITKVANVELCYRALQFYLDYKPLLINDLLLVLSPRLDHTWTVSFFS
  KAGQLPLVKPYLRSVQSHNNKSVNEALNHLLTEEEDYQGLRASIDAYDNFDNISLAQQLE
  KHQLMEFRCIAAYLYKGNNWWAQSVELCKKDHLYKDAMQHAAESRDAELAQKLLQWFLEE
  GKRECFAACLFTCYDLLRPDMVLELAWRHNLVDLAMPYFIQVMREYLSKVDKLDALESLR
  KQEEHVTEPAPLVFDFDGHE
• Function: Clathrin is the major protein of the polyhedral coat of coated pits and vesicles. Two different adapter protein complexes link the clathrin lattice either to the plasma membrane or to the trans-Golgi network.
• Tissue Specificity: Maximal levels in skeletal muscle. High levels in heart and testis. Low expression detected in all other tissues.
• KEGG Pathway:
  Lysosome (hsa04142)
  Endocytosis (hsa04144)
  Sy.ptic vesicle cycle (hsa04721)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Huntington disease (hsa05016)
  Bacterial invasion of epithelial cells (hsa05100)
• Reactome Pathway:
  Formation of annular gap junctions (R-HSA-196025)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Gap junction degradation (R-HSA-190873)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anaplastic large cell lymphoma	DISP4D1R	Strong	Genetic Variation	[1]
Meningioma	DISPT4TG	moderate	Biomarker	[2]
Neoplasm	DISZKGEW	moderate	Biomarker	[2]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[3]
Congenital insensitivity to pain with severe intellectual disability	DISSPS92	Supportive	Autosomal recessive	[4]
Multiple congenital anomalies/dysmorphic syndrome	DIS0LF2K	Limited	Autosomal dominant	[5]

8 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 Clathrin heavy chain 2 (CLTCL1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Clathrin heavy chain 2 (CLTCL1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Clathrin heavy chain 2 (CLTCL1).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Clathrin heavy chain 2 (CLTCL1).	[9]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Clathrin heavy chain 2 (CLTCL1).	[10]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Clathrin heavy chain 2 (CLTCL1).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Clathrin heavy chain 2 (CLTCL1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Clathrin heavy chain 2 (CLTCL1).	[15]

3 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 decreases the methylation of Clathrin heavy chain 2 (CLTCL1).	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Clathrin heavy chain 2 (CLTCL1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Clathrin heavy chain 2 (CLTCL1).	[16]

References

• [1] Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor.Genes Chromosomes Cancer. 2002 Aug;34(4):354-62. doi: 10.1002/gcc.10033.
• [2] Characterization of a second human clathrin heavy chain polypeptide gene (CLH-22) from chromosome 22q11.Hum Mol Genet. 1996 May;5(5):625-31. doi: 10.1093/hmg/5.5.625.
• [3] The essential role of clathrin-mediated endocytosis in the infectious entry of human enterovirus 71.J Biol Chem. 2011 Jan 7;286(1):309-21. doi: 10.1074/jbc.M110.168468. Epub 2010 Oct 18.
• [4] A novel disorder reveals clathrin heavy chain-22 is essential for human pain and touch development. Brain. 2015 Aug;138(Pt 8):2147-60. doi: 10.1093/brain/awv149. Epub 2015 Jun 11.
• [5] 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.
• [6] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] 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.
• [8] 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.
• [9] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [10] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [11] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [12] 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.
• [13] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [14] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [15] 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.
• [16] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.