Details of Drug Off-Target (DOT)

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

• DOT Name: Caspase recruitment domain-containing protein 14 (CARD14)
• Synonyms: CARD-containing MAGUK protein 2; Carma 2
• Gene Name: CARD14
• Related Disease:
  Advanced cancer
  Dermatitis
  Fatal familial insomnia
  Palmoplantar pustulosis
  Tendinopathy
  Acquired immune deficiency syndrome
  Adult glioblastoma
  Amyloidosis
  Bernard-Soulier syndrome
  Breast carcinoma
  Chondrosarcoma
  Creutzfeldt Jacob disease
  Diphtheria
  Epithelial ovarian cancer
  Familial Mediterranean fever
  Familial pityriasis rubra pilaris
  Gerstmann-Straussler-Scheinker syndrome
  Glioblastoma multiforme
  Haemophilia A
  Hemophilia
  Hepatitis B virus infection
  Inflammatory bowel disease
  Influenza
  Knee osteoarthritis
  Neoplasm
  Osteoarthritis
  Prion disease
  Psoriasis 2
  Skin disease
  Synovitis
  Vitiligo
  Alopecia
  Androgenetic alopecia
  Juvenile idiopathic arthritis
  Moyamoya disease
  Pustular psoriasis
  Hepatocellular carcinoma
  Cutaneous squamous cell carcinoma
  Exanthem
  Gastric cancer
  Glaucoma/ocular hypertension
  High blood pressure
  Lateral meningocele syndrome
  Limb-mammary syndrome
  Meningitis
  Pityriasis rubra pilaris
  Stomach cancer
• UniProt ID: CAR14_HUMAN
• Pfam ID: PF00619
• Sequence:
  MGELCRRDSALTALDEETLWEMMESHRHRIVRCICPSRLTPYLRQAKVLCQLDEEEVLHS
  PRLTNSAMRAGHLLDLLKTRGKNGAIAFLESLKFHNPDVYTLVTGLQPDVDFSNFSGLME
  TSKLTECLAGAIGSLQEELNQEKGQKEVLLRRCQQLQEHLGLAETRAEGLHQLEADHSRM
  KREVSAHFHEVLRLKDEMLSLSLHYSNALQEKELAASRCRSLQEELYLLKQELQRANMVS
  SCELELQEQSLRTASDQESGDEELNRLKEENEKLRSLTFSLAEKDILEQSLDEARGSRQE
  LVERIHSLRERAVAAERQREQYWEEKEQTLLQFQKSKMACQLYREKVNALQAQVCELQKE
  RDQAYSARDSAQREISQSLVEKDSLRRQVFELTDQVCELRTQLRQLQAEPPGVLKQEART
  REPCPREKQRLVRMHAICPRDDSDCSLVSSTESQLLSDLSATSSRELVDSFRSSSPAPPS
  QQSLYKRVAEDFGEEPWSFSSCLEIPEGDPGALPGAKAGDPHLDYELLDTADLPQLESSL
  QPVSPGRLDVSESGVLMRRRPARRILSQVTMLAFQGDALLEQISVIGGNLTGIFIHRVTP
  GSAADQMALRPGTQIVMVDYEASEPLFKAVLEDTTLEEAVGLLRRVDGFCCLSVKVNTDG
  YKRLLQDLEAKVATSGDSFYIRVNLAMEGRAKGELQVHCNEVLHVTDTMFQGCGCWHAHR
  VNSYTMKDTAAHGTIPNYSRAQQQLIALIQDMTQQCTVTRKPSSGGPQKLVRIVSMDKAK
  ASPLRLSFDRGQLDPSRMEGSSTCFWAESCLTLVPYTLVRPHRPARPRPVLLVPRAVGKI
  LSEKLCLLQGFKKCLAEYLSQEEYEAWSQRGDIIQEGEVSGGRCWVTRHAVESLMEKNTH
  ALLDVQLDSVCTLHRMDIFPIVIHVSVNEKMAKKLKKGLQRLGTSEEQLLEAARQEEGDL
  DRAPCLYSSLAPDGWSDLDGLLSCVRQAIADEQKKVVWTEQSPR
• Function: Acts as a scaffolding protein that can activate the inflammatory transcription factor NF-kappa-B and p38/JNK MAP kinase signaling pathways. Forms a signaling complex with BCL10 and MALT1, and activates MALT1 proteolytic activity and inflammatory gene expression. MALT1 is indispensable for CARD14-induced activation of NF-kappa-B and p38/JNK MAP kinases. May play a role in signaling mediated by TRAF2, TRAF3 and TRAF6 and protects cells against apoptosis; [Isoform 3]: Not able to activate the inflammatory transcription factor NF-kappa-B and may function as a dominant negative regulator.
• Tissue Specificity: Isoform 1 is detected in placenta and epidermal keratinocytes . Isoform 2 is detected in leukocytes and fetal brain .
• KEGG Pathway: NF-kappa B sig.ling pathway (hsa04064)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Dermatitis	DISY5SZC	Definitive	Genetic Variation	[2]
Fatal familial insomnia	DIS1FL1J	Definitive	Genetic Variation	[3]
Palmoplantar pustulosis	DISCNSWD	Definitive	Biomarker	[4]
Tendinopathy	DISJH7UX	Definitive	Biomarker	[5]
Acquired immune deficiency syndrome	DISL5UOX	Strong	Biomarker	[6]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[7]
Amyloidosis	DISHTAI2	Strong	Biomarker	[8]
Bernard-Soulier syndrome	DISLD1FU	Strong	Biomarker	[9]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[10]
Chondrosarcoma	DIS4I7JB	Strong	Biomarker	[1]
Creutzfeldt Jacob disease	DISCB6RX	Strong	Genetic Variation	[11]
Diphtheria	DISZWM55	Strong	Genetic Variation	[12]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[13]
Familial Mediterranean fever	DISVP5WP	Strong	Genetic Variation	[14]
Familial pityriasis rubra pilaris	DISEKWY1	Strong	Autosomal dominant	[15]
Gerstmann-Straussler-Scheinker syndrome	DISIO6KC	Strong	Genetic Variation	[16]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[7]
Haemophilia A	DIS0RQ2E	Strong	Biomarker	[17]
Hemophilia	DIS1S8P6	Strong	Biomarker	[17]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[12]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[18]
Influenza	DIS3PNU3	Strong	Biomarker	[12]
Knee osteoarthritis	DISLSNBJ	Strong	Biomarker	[19]
Neoplasm	DISZKGEW	Strong	Biomarker	[20]
Osteoarthritis	DIS05URM	Strong	Biomarker	[21]
Prion disease	DISOUMB0	Strong	Genetic Variation	[22]
Psoriasis 2	DISPSDH8	Strong	Autosomal dominant	[15]
Skin disease	DISDW8R6	Strong	Genetic Variation	[23]
Synovitis	DISW2GPY	Strong	Biomarker	[24]
Vitiligo	DISR05SL	Strong	Biomarker	[25]
Alopecia	DIS37HU4	moderate	Biomarker	[26]
Androgenetic alopecia	DISSJR1P	moderate	Biomarker	[26]
Juvenile idiopathic arthritis	DISQZGBV	moderate	Biomarker	[21]
Moyamoya disease	DISO62CA	moderate	Genetic Variation	[27]
Pustular psoriasis	DISXOG13	moderate	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Disputed	Biomarker	[28]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Altered Expression	[29]
Exanthem	DISAFOQN	Limited	Biomarker	[30]
Gastric cancer	DISXGOUK	Limited	Biomarker	[31]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[32]
High blood pressure	DISY2OHH	Limited	Biomarker	[33]
Lateral meningocele syndrome	DISG74RP	Limited	Biomarker	[34]
Limb-mammary syndrome	DIS7H4FP	Limited	Biomarker	[34]
Meningitis	DISQABAA	Limited	Biomarker	[35]
Pityriasis rubra pilaris	DISVC72D	Limited	Genetic Variation	[36]
Stomach cancer	DISKIJSX	Limited	Biomarker	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Caspase recruitment domain-containing protein 14 (CARD14).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Caspase recruitment domain-containing protein 14 (CARD14).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Caspase recruitment domain-containing protein 14 (CARD14).	[38]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Caspase recruitment domain-containing protein 14 (CARD14).	[39]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Caspase recruitment domain-containing protein 14 (CARD14).	[41]

References

• [1] PRP? significantly decreases the ALDHhigh cancer stem cell population and regulates the aberrant Wnt/catenin pathway in human chondrosarcoma JJ012cells.Oncol Rep. 2019 Jul;42(1):103-114. doi: 10.3892/or.2019.7172. Epub 2019 May 24.
• [2] Gain of function p.E138A alteration in Card14 leads to psoriasiform skin inflammation and implicates genetic modifiers in disease severity.Exp Mol Pathol. 2019 Oct;110:104286. doi: 10.1016/j.yexmp.2019.104286. Epub 2019 Jul 16.
• [3] Structural facets of disease-linked human prion protein mutants: a molecular dynamic study.Proteins. 2010 Dec;78(16):3270-80. doi: 10.1002/prot.22834.
• [4] Autoinflammatory keratinization diseases: An emerging concept encompassing various inflammatory keratinization disorders of the skin.J Dermatol Sci. 2018 May;90(2):105-111. doi: 10.1016/j.jdermsci.2018.01.012. Epub 2018 Feb 1.
• [5] Intratendon delivery of leukocyte-rich platelet-rich plasma at early stage promotes tendon repair in a rabbit Achilles tendinopathy model.J Tissue Eng Regen Med. 2020 Mar;14(3):452-463. doi: 10.1002/term.3006. Epub 2019 Dec 23.
• [6] The application of L-PRP in AIDS patients with crural chronic ulcers: A pilot study.Adv Med Sci. 2018 Mar;63(1):140-146. doi: 10.1016/j.advms.2017.10.002. Epub 2017 Nov 6.
• [7] Epigenetic regulation of embryonic stem cell marker miR302C in human chondrosarcoma as determinant of antiproliferative activity of proline-rich polypeptide 1.Int J Oncol. 2015 Aug;47(2):465-72. doi: 10.3892/ijo.2015.3054. Epub 2015 Jun 18.
• [8] Pro-Inflammatory S100A9 Protein Aggregation Promoted by NCAM1 Peptide Constructs.ACS Chem Biol. 2019 Jul 19;14(7):1410-1417. doi: 10.1021/acschembio.9b00394. Epub 2019 Jun 13.
• [9] Fibrin polymerization is crucial for thrombin generation in platelet-rich plasma in a VWF-GPIb-dependent process, defective in Bernard-Soulier syndrome.J Thromb Haemost. 2004 Jan;2(1):170-6. doi: 10.1111/j.1538-7836.2004.00558.x.
• [10] Cytostatic effect of novel mTOR inhibitor, PRP-1 (galarmin) in MDA 231 (ER-) breast carcinoma cell line. PRP-1 inhibits mesenchymal tumors.Tumour Biol. 2011 Aug;32(4):745-51. doi: 10.1007/s13277-011-0176-3. Epub 2011 Apr 15.
• [11] An autopsy case of Creutzfeldt-Jakob disease with a V180I mutation of the PrP gene and Alzheimer-type pathology.Neuropathology. 2010 Apr;30(2):159-64. doi: 10.1111/j.1440-1789.2009.01048.x. Epub 2009 Aug 23.
• [12] Evaluation of a Hexavalent-Pentavalent-Hexavalent Infant Primary Vaccination Series Followed by a Pentavalent Booster Vaccine in Healthy Infants and Toddlers.Pediatr Infect Dis J. 2019 Mar;38(3):317-322. doi: 10.1097/INF.0000000000002231.
• [13] A formulation of pancreatic pro-enzymes provides potent anti-tumour efficacy: a pilot study focused on pancreatic and ovarian cancer.Sci Rep. 2017 Oct 25;7(1):13998. doi: 10.1038/s41598-017-14571-x.
• [14] Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study.Rheumatol Int. 2019 May;39(5):911-919. doi: 10.1007/s00296-019-04252-5. Epub 2019 Feb 19.
• [15] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [16] Gerstmann-Strussler-Scheinker disease revisited: accumulation of covalently-linked multimers of internal prion protein fragments.Acta Neuropathol Commun. 2019 May 29;7(1):85. doi: 10.1186/s40478-019-0734-2.
• [17] Haemophilic arthropathy: A narrative review on the use of intra-articular drugs for arthritis.Haemophilia. 2019 Nov;25(6):919-927. doi: 10.1111/hae.13857. Epub 2019 Oct 22.
• [18] Caspase recruitment domain (CARD) family (CARD9, CARD10, CARD11, CARD14 and CARD15) are increased during active inflammation in patients with inflammatory bowel disease.J Inflamm (Lond). 2018 Jul 11;15:13. doi: 10.1186/s12950-018-0189-4. eCollection 2018.
• [19] The use of cellular matrix in symptomatic knee osteoarthritis.Bosn J Basic Med Sci. 2020 May 1;20(2):271-274. doi: 10.17305/bjbms.2019.4205.
• [20] Toll like receptors TLR1/2, TLR6 and MUC5B as binding interaction partners with cytostatic proline rich polypeptide 1 in human chondrosarcoma.Int J Oncol. 2018 Jan;52(1):139-154. doi: 10.3892/ijo.2017.4199. Epub 2017 Nov 9.
• [21] Comparative analysis of conventional and biological treatment in healing of bone disease.Saudi J Biol Sci. 2018 Jan;25(1):162-166. doi: 10.1016/j.sjbs.2017.02.003. Epub 2017 Feb 24.
• [22] PrP(ST), a soluble, protease resistant and truncated PrP form features in the pathogenesis of a genetic prion disease.PLoS One. 2013 Jul 26;8(7):e69583. doi: 10.1371/journal.pone.0069583. Print 2013.
• [23] CARD14/CARMA2sh and TANK differentially regulate poly(I:C)-induced inflammatory reaction in keratinocytes.J Cell Physiol. 2020 Mar;235(3):1895-1902. doi: 10.1002/jcp.29161. Epub 2019 Sep 4.
• [24] Intra-Articular Injections of a Whole Blood Clot Secretome, Autologous Conditioned Serum, Have Superior Clinical and Biochemical Efficacy Over Platelet-Rich Plasma and Induce Rejuvenation-Associated Changes of Joint Metabolism: A Prospective, Controlled Open-Label Clinical Study in Chronic Knee Osteoarthritis.Rejuvenation Res. 2020 Oct;23(5):401-410. doi: 10.1089/rej.2019.2263. Epub 2020 Feb 10.
• [25] Evaluation of combined excimer laser and platelet-rich plasma for the treatment of nonsegmental vitiligo: A prospective comparative study.J Cosmet Dermatol. 2020 Apr;19(4):869-877. doi: 10.1111/jocd.13103. Epub 2019 Sep 21.
• [26] Mechanical and Controlled PRP Injections in Patients Affected by Androgenetic Alopecia.J Vis Exp. 2018 Jan 27;(131):56406. doi: 10.3791/56406.
• [27] Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study.Stroke. 2018 Jan;49(1):11-18. doi: 10.1161/STROKEAHA.117.017430.
• [28] Short Proline-Rich Lipopeptide Potentiates Minocycline and Rifampin against Multidrug- and Extensively Drug-Resistant Pseudomonas aeruginosa.Antimicrob Agents Chemother. 2018 Mar 27;62(4):e02374-17. doi: 10.1128/AAC.02374-17. Print 2018 Apr.
• [29] Novel CARD11 Mutations in Human Cutaneous Squamous Cell Carcinoma Lead to Aberrant NF-B Regulation.Am J Pathol. 2015 Sep;185(9):2354-63. doi: 10.1016/j.ajpath.2015.05.018. Epub 2015 Jul 26.
• [30] Histopathologic findings characteristic of CARD14-associated papulosquamous eruption.J Cutan Pathol. 2020 May;47(5):425-430. doi: 10.1111/cup.13633. Epub 2019 Dec 26.
• [31] Lipid insertion enables targeted functionalization of paclitaxel-loaded erythrocyte membrane nanosystem by tumor-penetrating bispecific recombinant protein.Int J Nanomedicine. 2018 Sep 11;13:5347-5359. doi: 10.2147/IJN.S165109. eCollection 2018.
• [32] Treatment of chronic and extreme ocular hypotension following glaucoma surgery with intraocular platelet-rich plasma: A case report.Eur J Ophthalmol. 2019 Jul;29(4):NP9-NP12. doi: 10.1177/1120672118803515. Epub 2018 Oct 7.
• [33] Risk Factors of Neovascular Glaucoma After 25-gauge Vitrectomy for Proliferative Diabetic Retinopathy with Vitreous Hemorrhage: A Retrospective Multicenter Study.Sci Rep. 2019 Oct 16;9(1):14858. doi: 10.1038/s41598-019-51411-6.
• [34] Lenz-Majewski mutations in PTDSS1 affect phosphatidylinositol 4-phosphate metabolism at ER-PM and ER-Golgi junctions.Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4314-9. doi: 10.1073/pnas.1525719113. Epub 2016 Apr 4.
• [35] Epidemiological profile of meningitis in Iran before pentavalent vaccine introduction.BMC Pediatr. 2019 Oct 22;19(1):370. doi: 10.1186/s12887-019-1741-y.
• [36] The management and genetic background of pityriasis rubra pilaris: a single-centre experience.J Eur Acad Dermatol Venereol. 2019 May;33(5):944-949. doi: 10.1111/jdv.15455. Epub 2019 Mar 3.
• [37] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [38] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [39] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [40] 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.
• [41] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.