Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFNQ1ZU)

• DOT Name: Protein transport protein Sec16A (SEC16A)
• Synonyms: SEC16 homolog A; p250
• Gene Name: SEC16A
• Related Disease:
  Cutaneous squamous cell carcinoma
  Breast cancer
  Obesity
  Sarcoidosis
  Melanoma
  Parkinson disease
  Squamous cell carcinoma
• UniProt ID: SC16A_HUMAN
• Pfam ID: PF12932 ; PF12931
• Sequence:
  MQPPPQTVPSGMAGPPPAGNPRSVFWASSPYRRRANNNAAVAPTTCPLQPVTDPFAFSRQ
  ALQSTPLGSSSKSSPPVLQGPAPAGFSQHPGLLVPHTHARDSSQGPCEPLPGPLTQPRAH
  ASPFSGALTPSAPPGPEMNRSAEVGPSSEPEVQTLPYLPHYIPGVDPETSHGGHPHGNMP
  GLDRPLSRQNPHDGVVTPAASPSLPQPGLQMPGQWGPVQGGPQPSGQHRSPCPEGPVPSG
  VPCATSVPHFPTPSILHQGPGHEQHSPLVAPPAALPSDGRDEVSHLQSGSHLANNSDPES
  TFRQNPRIVNHWASPELRQNPGVKNEHRPASALVNPLARGDSPENRTHHPLGAGAGSGCA
  PLEADSGASGALAMFFQGGETENEENLSSEKAGLSGQADFDDFCSSPGLGRPPAPTHVGA
  GSLCQALLPGPSNEAAGDVWGDTASTGVPDASGSQYENVENLEFVQNQEVLPSEPLNLDP
  SSPSDQFRYGPLPGPAVPRHGAVCHTGAPDATLHTVHPDSVSSSYSSRSHGRLSGSARPQ
  ELVGTFIQQEVGKPEDEASGSFFKQIDSSPVGGETDETTVSQNYRGSVSQPSTPSPPKPT
  GIFQTSANSSFEPVKSHLVGVKPFEADRANVVGEVRETCVRQKQCRPAAALPDASPGNLE
  QPPDNMETLCAPQVCPLPLNSTTEAVHMLPHAGAPPLDTVYPAPEKRPSARTQGPVKCES
  PATTLWAQSELPDFGGNVLLAPAAPALYVCAKPQPPVVQPPEEAMSGQQSRNPSSAAPVQ
  SRGGIGASENLENPPKMGEEEALQSQASSGYASLLSSPPTESLQNPPVLIAQPDHSYNLA
  QPINFSVSLSNSHEKNQSWREALVGDRPAVSSWALGGDSGENTSLSGIPTSSVLSLSLPS
  SVAQSNFPQGSGASEMVSNQPANLLVQPPSQPVPENLVPESQKDRKAGSALPGFANSPAG
  STSVVLVPPAHGTLVPDGNKANHSSHQEDTYGALDFTLSRTLENPVNVYNPSHSDSLASQ
  QSVASHPRQSGPGAPNLDRFYQQVTKDAQGQPGLERAQQELVPPQQQASPPQLPKAMFSE
  LSNPESLPAQGQAQNSAQSPASLVLVDAGQQLPPRPPQSSSVSLVSSGSGQAAVPSEQPW
  PQPVPALAPGPPPQDLAAYYYYRPLYDAYQPQYSLPYPPEPGAASLYYQDVYSLYEPRYR
  PYDGAASAYAQNYRYPEPERPSSRASHSSERPPPRQGYPEGYYSSKSGWSSQSDYYASYY
  SSQYDYGDPGHWDRYHYSARVRDPRTYDRRYWCDAEYDAYRREHSAFGDRPEKRDNNWRY
  DPRFTGSFDDDPDPHRDPYGEEVDRRSVHSEHSARSLHSAHSLASRRSSLSSHSHQSQIY
  RSHNVAAGSYEAPLPPGSFHGDFAYGTYRSNFSSGPGFPEYGYPADTVWPAMEQVSSRPT
  SPEKFSVPHVCARFGPGGQLIKVIPNLPSEGQPALVEVHSMEALLQHTSEQEEMRAFPGP
  LAKDDTHKVDVINFAQNKAMKCLQNENLIDKESASLLWNFIVLLCRQNGTVVGTDIAELL
  LRDHRTVWLPGKSPNEANLIDFTNEAVEQVEEEESGEAQLSFLTGGPAAAASSLERETER
  FRELLLYGRKKDALESAMKNGLWGHALLLASKMDSRTHARVMTRFANSLPINDPLQTVYQ
  LMSGRMPAASTCCGDEKWGDWRPHLAMVLSNLNNNMDVESRTMATMGDTLASRGLLDAAH
  FCYLMAQAGFGVYTKKTTKLVLIGSNHSLPFLKFATNEAIQRTEAYEYAQSLGAETCPLP
  SFQVFKFIYSCRLAEMGLATQAFHYCEAIAKSILTQPHLYSPVLISQLVQMASQLRLFDP
  QLKEKPEEESLAAPTWLVHLQQVERQIKEGAGVWHQDGALPQQCPGTPSSEMEQLDRPGL
  SQPGALGIANPLLAVPAPSPEHSSPSVRLLPSAPQTLPDGPLASPARVPMFPVPLPPGPL
  EPGPGCVTPGPALGFLEPSGPGLPPGVPPLQERRHLLQEARSPDPGIVPQEAPVGNSLSE
  LSEENFDGKFANLTPSRTVPDSEAPPGWDRADSGPTQPPLSLSPAPETKRPGQAAKKETK
  EPKKGESWFFRWLPGKKKTEAYLPDDKNKSIVWDEKKNQWVNLNEPEEEKKAPPPPPTSM
  PKTVQAAPPALPGPPGAPVNMYSRRAAGTRARYVDVLNPSGTQRSEPALAPADFVAPLAP
  LPIPSNLFVPTPDAEEPQLPDGTGREGPAAARGLANPEPAPEPKVLSSAASLPGSELPSS
  RPEGSQGGELSRCSSMSSLSREVSQHFNQAPGDLPAAGGPPSGAMPFYNPAQLAQACATS
  GSSRLGRIGQRKHLVLN
• Function: Acts as a molecular scaffold that plays a key role in the organization of the endoplasmic reticulum exit sites (ERES), also known as transitional endoplasmic reticulum (tER). SAR1A-GTP-dependent assembly of SEC16A on the ER membrane forms an organized scaffold defining an ERES. Required for secretory cargo traffic from the endoplasmic reticulum to the Golgi apparatus. Mediates the recruitment of MIA3/TANGO to ERES. Regulates both conventional (ER/Golgi-dependent) and GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of CFTR to cell membrane. Positively regulates the protein stability of E3 ubiquitin-protein ligases RNF152 and RNF183 and the ER localization of RNF183. Acts as a RAB10 effector in the regulation of insulin-induced SLC2A4/GLUT4 glucose transporter-enriched vesicles delivery to the cell membrane in adipocytes.
• Tissue Specificity: Ubiquitous. Expressed at higher levels in the pancreas.
• Reactome Pathway: COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cutaneous squamous cell carcinoma	DIS3LXUG	Definitive	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Obesity	DIS47Y1K	Strong	Genetic Variation	[3]
Sarcoidosis	DISE5B8Z	Strong	Biomarker	[4]
Melanoma	DIS1RRCY	Limited	Biomarker	[1]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[5]
Squamous cell carcinoma	DISQVIFL	Limited	Genetic Variation	[6]

4 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 Protein transport protein Sec16A (SEC16A).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Protein transport protein Sec16A (SEC16A).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein transport protein Sec16A (SEC16A).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Protein transport protein Sec16A (SEC16A).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein transport protein Sec16A (SEC16A).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein transport protein Sec16A (SEC16A).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein transport protein Sec16A (SEC16A).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein transport protein Sec16A (SEC16A).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein transport protein Sec16A (SEC16A).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein transport protein Sec16A (SEC16A).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein transport protein Sec16A (SEC16A).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein transport protein Sec16A (SEC16A).	[15]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Protein transport protein Sec16A (SEC16A).	[16]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Protein transport protein Sec16A (SEC16A).	[17]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Protein transport protein Sec16A (SEC16A).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Protein transport protein Sec16A (SEC16A).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Protein transport protein Sec16A (SEC16A).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Protein transport protein Sec16A (SEC16A).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein transport protein Sec16A (SEC16A).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein transport protein Sec16A (SEC16A).	[14]

References

• [1] Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma.Nat Commun. 2016 Jul 18;7:12048. doi: 10.1038/ncomms12048.
• [2] Are breast cancers driven by fusion genes?.Breast Cancer Res. 2012 Mar 16;14(2):303. doi: 10.1186/bcr3122.
• [3] Association study of common polymorphisms in MSRA, TFAP2B, MC4R, NRXN3, PPARGC1A, TMEM18, SEC16B, HOXB5 and OLFM4 genes with obesity-related traits among Portuguese children.J Hum Genet. 2014 Jun;59(6):307-13. doi: 10.1038/jhg.2014.23. Epub 2014 Mar 27.
• [4] Whole exome sequencing in three families segregating a pediatric case of sarcoidosis.BMC Med Genomics. 2018 Mar 6;11(1):23. doi: 10.1186/s12920-018-0338-x.
• [5] Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.EMBO J. 2014 Oct 16;33(20):2314-31. doi: 10.15252/embj.201487807. Epub 2014 Sep 8.
• [6] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [14] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [15] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [16] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [21] 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.
• [22] 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.