Details of Drug Off-Target (DOT)

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

• DOT Name: Caspase recruitment domain-containing protein 11 (CARD11)
• Synonyms: CARD-containing MAGUK protein 1; Carma 1
• Gene Name: CARD11
• Related Disease:
  BENTA disease
  Epithelial ovarian cancer
  Immunodeficiency 11b with atopic dermatitis
  Nervous system disease
  Severe combined immunodeficiency due to CARD11 deficiency
  T-cell acute lymphoblastic leukaemia
  Adult lymphoma
  Advanced cancer
  Autoimmune disease
  B-cell lymphoma
  B-cell neoplasm
  Central nervous system lymphoma
  Clear cell renal carcinoma
  Common variable immunodeficiency
  Endometriosis
  Follicular lymphoma
  Glioma
  Inborn error of immunity
  Inflammatory bowel disease
  Lymphoma
  Lymphoma, non-Hodgkin, familial
  Lymphoproliferative syndrome
  Mantle cell lymphoma
  Marginal zone lymphoma
  Multiple sclerosis
  Neoplasm
  Non-hodgkin lymphoma
  Papillary renal cell carcinoma
  Pediatric lymphoma
  Pelvic inflammatory disease
  Pneumonia
  Pneumonitis
  Primary cutaneous T-cell lymphoma
  Renal cell carcinoma
  Sezary syndrome
  Small lymphocytic lymphoma
  Adult T-cell leukemia/lymphoma
  Immunodeficiency
  Severe combined immunodeficiency
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Ankylosing spondylitis
  Atopic dermatitis
  Cutaneous squamous cell carcinoma
  Marinesco-Sjogren syndrome
  Tuberculosis
• UniProt ID: CAR11_HUMAN
• PDB ID: 4JUP; 4LWD
• Pfam ID: PF00619
• Sequence:
  MPGGGPEMDDYMETLKDEEDALWENVECNRHMLSRYINPAKLTPYLRQCKVIDEQDEDEV
  LNAPMLPSKINRAGRLLDILHTKGQRGYVVFLESLEFYYPELYKLVTGKEPTRRFSTIVV
  EEGHEGLTHFLMNEVIKLQQQMKAKDLQRCELLARLRQLEDEKKQMTLTRVELLTFQERY
  YKMKEERDSYNDELVKVKDDNYNLAMRYAQLSEEKNMAVMRSRDLQLEIDQLKHRLNKME
  EECKLERNQSLKLKNDIENRPKKEQVLELERENEMLKTKNQELQSIIQAGKRSLPDSDKA
  ILDILEHDRKEALEDRQELVNRIYNLQEEARQAEELRDKYLEEKEDLELKCSTLGKDCEM
  YKHRMNTVMLQLEEVERERDQAFHSRDEAQTQYSQCLIEKDKYRKQIRELEEKNDEMRIE
  MVRREACIVNLESKLRRLSKDSNNLDQSLPRNLPVTIISQDFGDASPRTNGQEADDSSTS
  EESPEDSKYFLPYHPPQRRMNLKGIQLQRAKSPISLKRTSDFQAKGHEEEGTDASPSSCG
  SLPITNSFTKMQPPRSRSSIMSITAEPPGNDSIVRRYKEDAPHRSTVEEDNDSGGFDALD
  LDDDSHERYSFGPSSIHSSSSSHQSEGLDAYDLEQVNLMFRKFSLERPFRPSVTSVGHVR
  GPGPSVQHTTLNGDSLTSQLTLLGGNARGSFVHSVKPGSLAEKAGLREGHQLLLLEGCIR
  GERQSVPLDTCTKEEAHWTIQRCSGPVTLHYKVNHEGYRKLVKDMEDGLITSGDSFYIRL
  NLNISSQLDACTMSLKCDDVVHVRDTMYQDRHEWLCARVDPFTDHDLDMGTIPSYSRAQQ
  LLLVKLQRLMHRGSREEVDGTHHTLRALRNTLQPEEALSTSDPRVSPRLSRASFLFGQLL
  QFVSRSENKYKRMNSNERVRIISGSPLGSLARSSLDATKLLTEKQEELDPESELGKNLSL
  IPYSLVRAFYCERRRPVLFTPTVLAKTLVQRLLNSGGAMEFTICKSDIVTRDEFLRRQKT
  ETIIYSREKNPNAFECIAPANIEAVAAKNKHCLLEAGIGCTRDLIKSNIYPIVLFIRVCE
  KNIKRFRKLLPRPETEEEFLRVCRLKEKELEALPCLYATVEPDMWGSVEELLRVVKDKIG
  EEQRKTIWVDEDQL
• Function: Adapter protein that plays a key role in adaptive immune response by transducing the activation of NF-kappa-B downstream of T-cell receptor (TCR) and B-cell receptor (BCR) engagement. Transduces signals downstream TCR or BCR activation via the formation of a multiprotein complex together with BCL10 and MALT1 that induces NF-kappa-B and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways. Upon activation in response to TCR or BCR triggering, CARD11 homooligomerizes to form a nucleating helical template that recruits BCL10 via CARD-CARD interaction, thereby promoting polymerization of BCL10 and subsequent recruitment of MALT1: this leads to I-kappa-B kinase (IKK) phosphorylation and degradation, and release of NF-kappa-B proteins for nuclear translocation. Its binding to DPP4 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner. Promotes linear ubiquitination of BCL10 by promoting the targeting of BCL10 to RNF31/HOIP. Stimulates the phosphorylation of BCL10. Also activates the TORC1 signaling pathway.
• Tissue Specificity: Detected in adult peripheral blood leukocytes, thymus, spleen and liver. Also found in promyelocytic leukemia HL-60 cells, chronic myelogenous leukemia K-562 cells, Burkitt's lymphoma Raji cells and colorectal adenocarcinoma SW480 cells. Not detected in HeLaS3, MOLT-4, A-549 and G431 cells.
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
• Reactome Pathway:
  Downstream TCR signaling (R-HSA-202424)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
BENTA disease	DISHWIL6	Definitive	Autosomal dominant	[1]
Epithelial ovarian cancer	DIS56MH2	Definitive	Genetic Variation	[2]
Immunodeficiency 11b with atopic dermatitis	DISTM4QL	Definitive	Autosomal dominant	[1]
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[3]
Severe combined immunodeficiency due to CARD11 deficiency	DISEZ5L1	Definitive	Autosomal recessive	[1]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Altered Expression	[4]
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[7]
B-cell lymphoma	DISIH1YQ	Strong	Genetic Variation	[8]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[9]
Central nervous system lymphoma	DISBYQTA	Strong	Biomarker	[10]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[11]
Common variable immunodeficiency	DISHE7JQ	Strong	Biomarker	[12]
Endometriosis	DISX1AG8	Strong	Genetic Variation	[13]
Follicular lymphoma	DISVEUR6	Strong	Biomarker	[14]
Glioma	DIS5RPEH	Strong	Altered Expression	[15]
Inborn error of immunity	DISNGCMN	Strong	Genetic Variation	[16]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[17]
Lymphoma	DISN6V4S	Strong	Biomarker	[18]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Genetic Variation	[16]
Lymphoproliferative syndrome	DISMVL8O	Strong	Biomarker	[19]
Mantle cell lymphoma	DISFREOV	Strong	Biomarker	[20]
Marginal zone lymphoma	DISLZ4AO	Strong	Biomarker	[21]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[22]
Neoplasm	DISZKGEW	Strong	Biomarker	[23]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[16]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[11]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[5]
Pelvic inflammatory disease	DISWQR4J	Strong	Biomarker	[24]
Pneumonia	DIS8EF3M	Strong	Biomarker	[25]
Pneumonitis	DIS88E0K	Strong	Biomarker	[25]
Primary cutaneous T-cell lymphoma	DIS35WVW	Strong	Biomarker	[26]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[11]
Sezary syndrome	DISFMTC7	Strong	Biomarker	[27]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[28]
Adult T-cell leukemia/lymphoma	DIS882XU	moderate	Biomarker	[29]
Immunodeficiency	DIS093I0	moderate	Genetic Variation	[30]
Severe combined immunodeficiency	DIS6MF4Q	moderate	Genetic Variation	[31]
Thyroid cancer	DIS3VLDH	moderate	Altered Expression	[32]
Thyroid gland carcinoma	DISMNGZ0	moderate	Altered Expression	[32]
Thyroid tumor	DISLVKMD	moderate	Altered Expression	[32]
Ankylosing spondylitis	DISRC6IR	Limited	Biomarker	[33]
Atopic dermatitis	DISTCP41	Limited	Genetic Variation	[34]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Genetic Variation	[35]
Marinesco-Sjogren syndrome	DISKEU0B	Limited	Biomarker	[36]
Tuberculosis	DIS2YIMD	Limited	Genetic Variation	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Caspase recruitment domain-containing protein 11 (CARD11).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Caspase recruitment domain-containing protein 11 (CARD11).	[39]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Caspase recruitment domain-containing protein 11 (CARD11).	[40]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Caspase recruitment domain-containing protein 11 (CARD11).	[41]

References

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• [24] Hyper-IgE in the allergy clinic--when is it primary immunodeficiency?.Allergy. 2018 Nov;73(11):2122-2136. doi: 10.1111/all.13578. Epub 2018 Oct 2.
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• [31] Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease.J Allergy Clin Immunol. 2019 Apr;143(4):1482-1495. doi: 10.1016/j.jaci.2018.08.013. Epub 2018 Aug 28.
• [32] MiR-539 inhibits thyroid cancer cell migration and invasion by directly targeting CARMA1.Biochem Biophys Res Commun. 2015 Sep 4;464(4):1128-1133. doi: 10.1016/j.bbrc.2015.07.090. Epub 2015 Jul 20.
• [33] Identification of the key genes and long noncoding RNAs in ankylosing spondylitis using RNA sequencing.Int J Mol Med. 2019 Mar;43(3):1179-1192. doi: 10.3892/ijmm.2018.4038. Epub 2018 Dec 20.
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