Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV5S1J2)

• DOT Name: Capping protein, Arp2/3 and myosin-I linker protein 2 (CARMIL2)
• Synonyms: Capping protein regulator and myosin 1 linker 2; F-actin-uncapping protein RLTPR; Leucine-rich repeat-containing protein 16C; RGD, leucine-rich repeat, tropomodulin and proline-rich-containing protein
• Gene Name: CARMIL2
• Related Disease:
  Immunodeficiency
  Inborn error of immunity
  Inflammatory bowel disease
  Severe combined immunodeficiency due to CARMIL2 deficiency
  Primary cutaneous T-cell lymphoma
• UniProt ID: CARL2_HUMAN
• Pfam ID: PF17888 ; PF16000 ; PF13516
• Sequence:
  MAQTPDGISCELRGEITRFLWPKEVELLLKTWLPGEGAVQNHVLALLRWRAYLLHTTCLP
  LRVDCTFSYLEVQAMALQETPPQVTFELESLRELVLEFPGVAALEQLAQHVAAAIKKVFP
  RSTLGKLFRRPTPASMLARLERSSPSESTDPCSPCGGFLETYEALCDYNGFPFREEIQWD
  VDTIYHRQGCRHFSLGDFSHLGSRDLALSVAALSYNLWFRCLSCVDMKLSLEVSEQILHM
  MSQSSHLEELVLETCSLRGDFVRRLAQALAGHSSSGLRELSLAGNLLDDRGMTALSRHLE
  RCPGALRRLSLAQTGLTPRGMRALGRALATNAAFDSTLTHLDLSGNPGALGASEDSGGLY
  SFLSRPNVLSFLNLAGTDTALDTVRGCSVGGWMTGRADWRAGRGGLGPPAGVANSLPPQL
  FAAVSRGCCTSLTHLDASRNVFSRTKSRAAPAALQLFLSRARTLRHLGLAGCKLPPDALR
  ALLDGLALNTHLRDLHLDLSACELRSAGAQVIQDLVCDAGAVSSLDLADNGFGSDMVTLV
  LAIGRSRSLRHVALGRNFNVRCKETLDDVLHRIVQLMQDDDCPLQSLSVAESRLKLGASV
  LLRALATNPNLTALDISGNAMGDAGAKLLAKALRVNSRLRSVVWDRNHTSALGLLDVAQA
  LEQNHSLKAMPLPLNDVAQAQRSRPELTARAVHQIQACLLRNNRADPASSDHTTRLQPLG
  LVSDPSEQEVNELCQSVQEHVELLGCGAGPQGEAAVRQAEDAIQNANFSLSILPILYEAG
  SSPSHHWQLGQKLEGLLRQVGEVCRQDIQDFTQATLDTARSLCPQMLQGSSWREQLEGVL
  AGSRGLPELLPEQLLQDAFTRLRDMRLSITGTLAESIVAQALAGLSAARDQLVESLAQQA
  TVTMPPALPAPDGGEPSLLEPGELEGLFFPEEKEEEKEKDDSPPQKWPELSHGLHLVPFI
  HSAAEEAEPEPELAAPGEDAEPQAGPSARGSPSPAAPGPPAGPLPRMDLPLAGQPLRHPT
  RARPRPRRQHHHRPPPGGPQVPPALPQEGNGLSARVDEGVEEFFSKRLIQQDRLWAPEED
  PATEGGATPVPRTLRKKLGTLFAFKKPRSTRGPRTDLETSPGAAPRTRKTTFGDLLRPPT
  RPSRGEELGGAEGDTSSPDPAGRSRPRYTRDSKAYSMILLPAEEEATLGARPDKRRPLER
  GETELAPSFEQRVQVMLQRIGVSRGSGGAEGKRKQSKDGEIKKAGSDGDIMDSSTEAPPI
  SIKSRTHSVSADPSCRPGPGSQGPESATWKTLGQQLNAELRSRGWGQQDGPGPPSPGQSP
  SPCRTSPSPDSLGLPEDPCLGPRNEDGQLRPRPLSAGRRAVSVHEDQLQAPAERPLRLQR
  SPVLKRRPKLEAPPSPSLGSGLGTEPLPPQPTEPSSPERSPPSPATDQRGGGPNP
• Function: Cell membrane-cytoskeleton-associated protein that plays a role in the regulation of actin polymerization at the barbed end of actin filaments. Prevents F-actin heterodimeric capping protein (CP) activity at the leading edges of migrating cells, and hence generates uncapped barbed ends and enhances actin polymerization. Plays a role in cell protrusion formations; involved in cell polarity, lamellipodial assembly, membrane ruffling and macropinosome formations. Involved as well in cell migration and invadopodia formation during wound healing. Required for CD28-mediated stimulation of NF-kappa-B signaling, involved in naive T cells activation, maturation into T memory cells, and differentiation into T helper and T regulatory cells.
• Tissue Specificity: Expressed in all tissues tested, including thymus, spleen, colon, leukocytes, peripheral blood, skin, skin keratinocytes and skin fibroblasts. Strong expression is detected in naive and memory CD4+ and CD8+ T cells, naive and memory B cells, regulatory T cells and NK cells, whereas it is poorly expressed in monocytes .

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency	DIS093I0	Strong	Genetic Variation	[1]
Inborn error of immunity	DISNGCMN	Strong	Biomarker	[2]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[3]
Severe combined immunodeficiency due to CARMIL2 deficiency	DIS8J76W	Strong	Autosomal recessive	[4]
Primary cutaneous T-cell lymphoma	DIS35WVW	Disputed	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Capping protein, Arp2/3 and myosin-I linker protein 2 (CARMIL2).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Capping protein, Arp2/3 and myosin-I linker protein 2 (CARMIL2).	[8]

3 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 Capping protein, Arp2/3 and myosin-I linker protein 2 (CARMIL2).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Capping protein, Arp2/3 and myosin-I linker protein 2 (CARMIL2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Capping protein, Arp2/3 and myosin-I linker protein 2 (CARMIL2).	[7]

References

• [1] A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant.J Clin Immunol. 2019 May;39(4):430-439. doi: 10.1007/s10875-019-00631-6. Epub 2019 May 11.
• [2] A human immunodeficiency syndrome caused by mutations in CARMIL2.Nat Commun. 2017 Jan 23;8:14209. doi: 10.1038/ncomms14209.
• [3] CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease.Inflamm Bowel Dis. 2019 Oct 18;25(11):1788-1795. doi: 10.1093/ibd/izz103.
• [4] Dual T cell- and B cell-intrinsic deficiency in humans with biallelic RLTPR mutations. J Exp Med. 2016 Oct 17;213(11):2413-2435. doi: 10.1084/jem.20160576. Epub 2016 Sep 19.
• [5] Genomic analysis of 220 CTCLs identifies a novel recurrent gain-of-function alteration in RLTPR (p.Q575E).Blood. 2017 Sep 21;130(12):1430-1440. doi: 10.1182/blood-2017-02-768234. Epub 2017 Jul 10.
• [6] 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.
• [7] 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.
• [8] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [9] 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.