Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2I5DOW)

• DOT Name: Cerebral cavernous malformations 2 protein (CCM2)
• Synonyms: Malcavernin
• Gene Name: CCM2
• Related Disease:
  Cerebral cavernous malformation 2
  Medulloblastoma
  Neoplasm
  Birt-Hogg-Dube syndrome
  Capillary malformation-arteriovenous malformation 1
  Cerebral cavernous malformation 1
  Cerebral cavernous malformation 3
  Epilepsy
  Neuroblastic tumor
  Coronary heart disease
  Famililal cerebral cavernous malformations
  Neuroblastoma
• UniProt ID: CCM2_HUMAN
• PDB ID: 4FQN; 4TVQ; 4WJ7; 4Y5O; 4YKC; 4YKD; 4YL6
• Pfam ID: PF16545
• Sequence:
  MEEEGKKGKKPGIVSPFKRVFLKGEKSRDKKAHEKVTERRPLHTVVLSLPERVEPDRLLS
  DYIEKEVKYLGQLTSIPGYLNPSSRTEILHFIDNAKRAHQLPGHLTQEHDAVLSLSAYNV
  KLAWRDGEDIILRVPIHDIAAVSYVRDDAAHLVVLKTAQDPGISPSQSLCAESSRGLSAG
  SLSESAVGPVEACCLVILAAESKVAAEELCCLLGQVFQVVYTESTIDFLDRAIFDGASTP
  THHLSLHSDDSSTKVDIKETYEVEASTFCFPESVDVGGASPHSKTISESELSASATELLQ
  DYMLTLRTKLSSQEIQQFAALLHEYRNGASIHEFCINLRQLYGDSRKFLLLGLRPFIPEK
  DSQHFENFLETIGVKDGRGIITDSFGRHRRALSTTSSSTTNGNRATGSSDDRSAPSEGDE
  WDRMISDISSDIEALGCSMDQDSA
• Function: Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity. May act through the stabilization of endothelial cell junctions. May function as a scaffold protein for MAP2K3-MAP3K3 signaling. Seems to play a major role in the modulation of MAP3K3-dependent p38 activation induced by hyperosmotic shock.
• KEGG Pathway: Adherens junction (hsa04520)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebral cavernous malformation 2	DIS7DG9B	Definitive	Autosomal dominant	[1]
Medulloblastoma	DISZD2ZL	Definitive	Biomarker	[2]
Neoplasm	DISZKGEW	Definitive	Biomarker	[3]
Birt-Hogg-Dube syndrome	DISIN5TD	Strong	Genetic Variation	[4]
Capillary malformation-arteriovenous malformation 1	DISBGIEI	Strong	Biomarker	[5]
Cerebral cavernous malformation 1	DIST5TVM	Strong	Genetic Variation	[6]
Cerebral cavernous malformation 3	DISHAV0P	Strong	Genetic Variation	[6]
Epilepsy	DISBB28L	Strong	Genetic Variation	[7]
Neuroblastic tumor	DISKWPS1	Strong	Biomarker	[8]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[9]
Famililal cerebral cavernous malformations	DISP72I1	Supportive	Autosomal dominant	[10]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[8]

5 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 Cerebral cavernous malformations 2 protein (CCM2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cerebral cavernous malformations 2 protein (CCM2).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cerebral cavernous malformations 2 protein (CCM2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Cerebral cavernous malformations 2 protein (CCM2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cerebral cavernous malformations 2 protein (CCM2).	[15]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Cerebral cavernous malformations 2 protein (CCM2).	[16]

References

• [1] Large germline deletions and duplication in isolated cerebral cavernous malformation patients. Neurogenetics. 2007 Apr;8(2):149-53. doi: 10.1007/s10048-006-0076-7. Epub 2007 Jan 9.
• [2] STK25 protein mediates TrkA and CCM2 protein-dependent death in pediatric tumor cells of neural origin.J Biol Chem. 2012 Aug 24;287(35):29285-9. doi: 10.1074/jbc.C112.345397. Epub 2012 Jul 10.
• [3] Live or let die: CCM2 provides the link.Neuron. 2009 Sep 10;63(5):559-60. doi: 10.1016/j.neuron.2009.08.030.
• [4] Genetically diagnosed Birt-Hogg-Dub syndrome and familial cerebral cavernous malformations in the same individual: a case report.Fam Cancer. 2017 Jan;16(1):139-142. doi: 10.1007/s10689-016-9928-y.
• [5] Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet. 2003 Dec;73(6):1459-64. doi: 10.1086/380314. Epub 2003 Nov 17.
• [6] A novel large deletion in CCM1 gene in a Tunisian family.Rev Neurol (Paris). 2019 Mar;175(3):194-197. doi: 10.1016/j.neurol.2018.04.013. Epub 2018 Oct 9.
• [7] Identification of a novel CCM2 gene mutation in an Italian family with multiple cerebral cavernous malformations and epilepsy: a causative mutation?.Gene. 2013 Apr 25;519(1):202-7. doi: 10.1016/j.gene.2012.09.045. Epub 2012 Sep 19.
• [8] CCM2 mediates death signaling by the TrkA receptor tyrosine kinase.Neuron. 2009 Sep 10;63(5):585-91. doi: 10.1016/j.neuron.2009.08.020.
• [9] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [10] 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.
• [11] 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.
• [12] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [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] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.