Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ006UD)

• DOT Name: Protein DENND6B (DENND6B)
• Synonyms: DENN domain-containing protein 6B
• Gene Name: DENND6B
• Related Disease: Schizophrenia
• UniProt ID: DEN6B_HUMAN
• Pfam ID: PF02141
• Sequence:
  MDALLGTGPRRARGCLGAAGPTSSGRAARTPAAPWARFSAWLECVCVVTFDLELGQALEL
  VYPNDFRLTDKEKSSICYLSFPDSHSGCLGDTQFSFRMRQCGGQRSPWHADDRHYNSRAP
  VALQREPAHYFGYVYFRQVKDSSVKRGYFQKSLVLVSRLPFVRLFQALLSLIAPEYFDKL
  APCLEAVCSEIDQWPAPAPGQTLNLPVMGVVVQVRIPSRVDKSESSPPKQFDQENLLPAP
  VVLASVHELDLFRCFRPVLTHMQTLWELMLLGEPLLVLAPSPDVSSEMVLALTSCLQPLR
  FCCDFRPYFTIHDSEFKEFTTRTQAPPNVVLGVTNPFFIKTLQHWPHILRVGEPKMSGDL
  PKQVKLKKPSRLKTLDTKPGLYTAYTAHLHRDKALLKRLLKGVQKKRPSDVQSALLRRHL
  LELTQSFIIPLEHYMASLMPLQKSITPWKTPPQIQPFSQDDFLRSLEHAGPQLTCILKGD
  WLGLYRRFFKSPHFDGWYRQRHKEMALKLEALHLEAICEANIETWMKDKSEVEVVDLVLK
  LREKLVRAQGHQLPVKEATLQRAQLYIETVIGSLPKDLQAVLCPP
• Function: Guanine nucleotide exchange factor (GEF) for RAB14. Also has some, lesser GEF activity towards RAB35.
• Reactome Pathway: RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[1]

1 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 DENND6B (DENND6B).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein DENND6B (DENND6B).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein DENND6B (DENND6B).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein DENND6B (DENND6B).	[5]
Palbociclib	DMD7L94	Approved	Palbociclib increases the expression of Protein DENND6B (DENND6B).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein DENND6B (DENND6B).	[7]

References

• [1] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [2] 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.
• [3] 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.
• [4] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [5] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [6] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [7] 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.