Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB1DM2C)

• DOT Name: Caveolae-associated protein 4 (CAVIN4)
• Synonyms: Muscle-related coiled-coil protein; Muscle-restricted coiled-coil protein
• Gene Name: CAVIN4
• Related Disease:
  B-cell neoplasm
  Dilated cardiomyopathy
  Myopathy
  High blood pressure
  Neoplasm
  Rhabdomyosarcoma
  Arrhythmia
  Cardiomyopathy
• UniProt ID: CAVN4_HUMAN
• Pfam ID: PF15237
• Sequence:
  MEHNGSASNADKIHQNRLSSVTEDEDQDAALTIVTVLDKVASIVDSVQASQKRIEERHRE
  MENAIKSVQIDLLKLSQSHSNTGHIINKLFEKTRKVSAHIKDVKARVEKQQIHVKKVEVK
  QEEIMKKNKFRVVIFQEKFRCPTSLSVVKDRNLTENQEEDDDDIFDPPVDLSSDEEYYVE
  ESRSARLRKSGKEHIDNIKKAFSKENMQKTRQNLDKKVNRIRTRIVTPERRERLRQSGER
  LRQSGERLRQSGERFKKSISNAAPSKEAFKMRSLRKGKDRTVAEGEECAREMGVDIIARS
  ESLGPISELYSDELSEPEHEAARPVYPPHEGREIPTPEPLKVTFKSQVKVEDDESLLLDL
  KHSS
• Function: Modulates the morphology of formed caveolae in cardiomyocytes, but is not required for caveolar formation. Facilitates the recruitment of MAPK1/3 to caveolae within cardiomyocytes and regulates alpha-1 adrenergic receptor-induced hypertrophic responses in cardiomyocytes through MAPK1/3 activation. Contributes to proper membrane localization and stabilization of caveolin-3 (CAV3) in cardiomyocytes. Induces RHOA activation and activates NPPA transcription and myofibrillar organization through the Rho/ROCK signaling pathway.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Strong	Altered Expression	[1]
Dilated cardiomyopathy	DISX608J	Strong	Biomarker	[1]
Myopathy	DISOWG27	Strong	Biomarker	[2]
High blood pressure	DISY2OHH	moderate	Biomarker	[3]
Neoplasm	DISZKGEW	moderate	Altered Expression	[4]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[4]
Arrhythmia	DISFF2NI	Limited	Biomarker	[5]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Caveolae-associated protein 4 (CAVIN4).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Caveolae-associated protein 4 (CAVIN4).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Caveolae-associated protein 4 (CAVIN4).	[9]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Caveolae-associated protein 4 (CAVIN4).	[8]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Caveolae-associated protein 4 (CAVIN4).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Caveolae-associated protein 4 (CAVIN4).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Caveolae-associated protein 4 (CAVIN4).	[11]

References

• [1] Systems Network Genomic Analysis Reveals Cardioprotective Effect of MURC/Cavin-4 Deletion Against Ischemia/Reperfusion Injury.J Am Heart Assoc. 2019 Aug 6;8(15):e012047. doi: 10.1161/JAHA.119.012047. Epub 2019 Jul 31.
• [2] MURC/Cavin-4 and cavin family members form tissue-specific caveolar complexes.J Cell Biol. 2009 Jun 29;185(7):1259-73. doi: 10.1083/jcb.200903053. Epub 2009 Jun 22.
• [3] MURC deficiency in smooth muscle attenuates pulmonary hypertension.Nat Commun. 2016 Aug 22;7:12417. doi: 10.1038/ncomms12417.
• [4] MURC/cavin-4 Is Co-Expressed with Caveolin-3 in Rhabdomyosarcoma Tumors and Its Silencing Prevents Myogenic Differentiation in the Human Embryonal RD Cell Line.PLoS One. 2015 Jun 18;10(6):e0130287. doi: 10.1371/journal.pone.0130287. eCollection 2015.
• [5] MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance.Mol Cell Biol. 2008 May;28(10):3424-36. doi: 10.1128/MCB.02186-07. Epub 2008 Mar 10.
• [6] MURC/CAVIN-4 facilitates store-operated calcium entry in neonatal cardiomyocytes.Biochim Biophys Acta Mol Cell Res. 2019 Aug;1866(8):1249-1259. doi: 10.1016/j.bbamcr.2019.03.017. Epub 2019 Apr 2.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [9] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [10] 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.
• [11] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.