Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK66C40)

• DOT Name: TBC1 domain family member 4 (TBC1D4)
• Synonyms: Akt substrate of 160 kDa; AS160
• Gene Name: TBC1D4
• Related Disease:
  Hyperinsulinemia
  Atopic dermatitis
  Non-insulin dependent diabetes
  Obesity
  Polycystic ovarian syndrome
  Diabetic retinopathy
  Prediabetes syndrome
  Type-1/2 diabetes
• UniProt ID: TBCD4_HUMAN
• PDB ID: 3QYB; 7NIX
• Pfam ID: PF11830 ; PF00640 ; PF00566
• Sequence:
  MEPPSCIQDEPFPHPLEPEPGVSAQPGPGKPSDKRFRLWYVGGSCLDHRTTLPMLPWLMA
  EIRRRSQKPEAGGCGAPAAREVILVLSAPFLRCVPAPGAGASGGTSPSATQPNPAVFIFE
  HKAQHISRFIHNSHDLTYFAYLIKAQPDDPESQMACHVFRATDPSQVPDVISSIRQLSKA
  AMKEDAKPSKDNEDAFYNSQKFEVLYCGKVTVTHKKAPSSLIDDCMEKFSLHEQQRLKIQ
  GEQRGPDPGEDLADLEVVVPGSPGDCLPEEADGTDTHLGLPAGASQPALTSSRVCFPERI
  LEDSGFDEQQEFRSRCSSVTGVQRRVHEGSQKSQPRRRHASAPSHVQPSDSEKNRTMLFQ
  VGRFEINLISPDTKSVVLEKNFKDISSCSQGIKHVDHFGFICRESPEPGLSQYICYVFQC
  ASESLVDEVMLTLKQAFSTAAALQSAKTQIKLCEACPMHSLHKLCERIEGLYPPRAKLVI
  QRHLSSLTDNEQADIFERVQKMKPVSDQEENELVILHLRQLCEAKQKTHVHIGEGPSTIS
  NSTIPENATSSGRFKLDILKNKAKRSLTSSLENIFSRGANRMRGRLGSVDSFERSNSLAS
  EKDYSPGDSPPGTPPASPPSSAWQTFPEEDSDSPQFRRRAHTFSHPPSSTKRKLNLQDGR
  AQGVRSPLLRQSSSEQCSNLSSVRRMYKESNSSSSLPSLHTSFSAPSFTAPSFLKSFYQN
  SGRLSPQYENEIRQDTASESSDGEGRKRTSSTCSNESLSVGGTSVTPRRISWRQRIFLRV
  ASPMNKSPSAMQQQDGLDRNELLPLSPLSPTMEEEPLVVFLSGEDDPEKIEERKKSKELR
  SLWRKAIHQQILLLRMEKENQKLEASRDELQSRKVKLDYEEVGACQKEVLITWDKKLLNC
  RAKIRCDMEDIHTLLKEGVPKSRRGEIWQFLALQYRLRHRLPNKQQPPDISYKELLKQLT
  AQQHAILVDLGRTFPTHPYFSVQLGPGQLSLFNLLKAYSLLDKEVGYCQGISFVAGVLLL
  HMSEEQAFEMLKFLMYDLGFRKQYRPDMMSLQIQMYQLSRLLHDYHRDLYNHLEENEISP
  SLYAAPWFLTLFASQFSLGFVARVFDIIFLQGTEVIFKVALSLLSSQETLIMECESFENI
  VEFLKNTLPDMNTSEMEKIITQVFEMDISKQLHAYEVEYHVLQDELQESSYSCEDSETLE
  KLERANSQLKRQNMDLLEKLQVAHTKIQALESNLENLLTRETKMKSLIRTLEQEKMAYQK
  TVEQLRKLLPADALVNCDLLLRDLNCNPNNKAKIGNKP
• Function: May act as a GTPase-activating protein for RAB2A, RAB8A, RAB10 and RAB14. Isoform 2 promotes insulin-induced glucose transporter SLC2A4/GLUT4 translocation at the plasma membrane, thus increasing glucose uptake.
• Tissue Specificity: Widely expressed. Isoform 2 is the highest overexpressed in most tissues. Isoform 1 is highly expressed in skeletal muscle and heart, but was not detectable in the liver nor in adipose tissue. Isoform 2 is strongly expressed in adrenal and thyroid gland, and also in lung, kidney, colon, brain and adipose tissue. Isoform 2 is moderately expressed in skeletal muscle. Expressed in pancreatic Langerhans islets, including beta cells (at protein level). Expression is decreased by twofold in pancreatic islets in type 2 diabetes patients compared to control subjects. Up-regulated in T-cells from patients with atopic dermatitis.
• KEGG Pathway:
  Thyroid hormone sig.ling pathway (hsa04919)
  Insulin resistance (hsa04931)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway: Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperinsulinemia	DISIDWT6	Definitive	Biomarker	[1]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[3]
Obesity	DIS47Y1K	Strong	Genetic Variation	[3]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[4]
Diabetic retinopathy	DISHGUJM	Limited	Genetic Variation	[5]
Prediabetes syndrome	DISH2I53	Limited	Biomarker	[6]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[6]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	TBC1 domain family member 4 (TBC1D4) affects the response to substance of Topotecan.	[26]
Vinblastine	DM5TVS3	Approved	TBC1 domain family member 4 (TBC1D4) affects the response to substance of Vinblastine.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of TBC1 domain family member 4 (TBC1D4).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of TBC1 domain family member 4 (TBC1D4).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of TBC1 domain family member 4 (TBC1D4).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of TBC1 domain family member 4 (TBC1D4).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of TBC1 domain family member 4 (TBC1D4).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of TBC1 domain family member 4 (TBC1D4).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of TBC1 domain family member 4 (TBC1D4).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of TBC1 domain family member 4 (TBC1D4).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of TBC1 domain family member 4 (TBC1D4).	[15]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of TBC1 domain family member 4 (TBC1D4).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of TBC1 domain family member 4 (TBC1D4).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of TBC1 domain family member 4 (TBC1D4).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of TBC1 domain family member 4 (TBC1D4).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of TBC1 domain family member 4 (TBC1D4).	[14]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of TBC1 domain family member 4 (TBC1D4).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of TBC1 domain family member 4 (TBC1D4).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of TBC1 domain family member 4 (TBC1D4).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of TBC1 domain family member 4 (TBC1D4).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of TBC1 domain family member 4 (TBC1D4).	[21]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of TBC1 domain family member 4 (TBC1D4).	[24]
D-glucose	DMMG2TO	Investigative	D-glucose increases the phosphorylation of TBC1 domain family member 4 (TBC1D4).	[25]

References

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• [2] Upregulation of the transcript level of GTPase activating protein KIAA0603 in T cells from patients with atopic dermatitis.FEBS Lett. 2004 Aug 13;572(1-3):135-40. doi: 10.1016/j.febslet.2004.07.023.
• [3] RabGAPs in skeletal muscle function and exercise.J Mol Endocrinol. 2020 Jan;64(1):R1-R19. doi: 10.1530/JME-19-0143.
• [4] Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.Dan Med J. 2014 Jul;61(7):B4890.
• [5] Genome-wide association study in a Chinese population with diabetic retinopathy.Hum Mol Genet. 2013 Aug 1;22(15):3165-73. doi: 10.1093/hmg/ddt161. Epub 2013 Apr 4.
• [6] Toward Precision Medicine: TBC1D4 Disruption Is Common Among the Inuit and Leads to Underdiagnosis of Type 2 Diabetes.Diabetes Care. 2016 Nov;39(11):1889-1895. doi: 10.2337/dc16-0769. Epub 2016 Aug 25.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [16] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [17] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [18] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [19] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [25] Insulin and GH signaling in human skeletal muscle in vivo following exogenous GH exposure: impact of an oral glucose load. PLoS One. 2011 May 3;6(5):e19392. doi: 10.1371/journal.pone.0019392.
• [26] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.