Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL0S21W)

• DOT Name: Pleckstrin homology domain-containing family G member 5 (PLEKHG5)
• Synonyms: PH domain-containing family G member 5; Guanine nucleotide exchange factor 720; GEF720
• Gene Name: PLEKHG5
• Related Disease:
  Neuromuscular disease
  Advanced cancer
  Alzheimer disease
  Charcot-Marie-Tooth disease recessive intermediate C
  Dementia
  Glioma
  Motor neurone disease
  Multiple sclerosis
  Neuronopathy, distal hereditary motor, autosomal recessive 4
  Polycystic ovarian syndrome
  Neoplasm
  Neuroblastoma
  Coronary heart disease
  Distal hereditary motor neuropathy
  Non-insulin dependent diabetes
• UniProt ID: PKHG5_HUMAN
• Pfam ID: PF00621
• Sequence:
  MHYDGHVRFDLPPQGSVLARNVSTRSCPPRTSPAVDLEEEEEESSVDGKGDRKSTGLKLS
  KKKARRRHTDDPSKECFTLKFDLNVDIETEIVPAMKKKSLGEVLLPVFERKGIALGKVDI
  YLDQSNTPLSLTFEAYRFGGHYLRVKAPAKPGDEGKVEQGMKDSKSLSLPILRPAGTGPP
  ALERVDAQSRRESLDILAPGRRRKNMSEFLGEASIPGQEPPTPSSCSLPSGSSGSTNTGD
  SWKNRAASRFSGFFSSGPSTSAFGREVDKMEQLEGKLHTYSLFGLPRLPRGLRFDHDSWE
  EEYDEDEDEDNACLRLEDSWRELIDGHEKLTRRQCHQQEAVWELLHTEASYIRKLRVIIN
  LFLCCLLNLQESGLLCEVEAERLFSNIPEIAQLHRRLWASVMAPVLEKARRTRALLQPGD
  FLKGFKMFGSLFKPYIRYCMEEEGCMEYMRGLLRDNDLFRAYITWAEKHPQCQRLKLSDM
  LAKPHQRLTKYPLLLKSVLRKTEEPRAKEAVVAMIGSVERFIHHVNACMRQRQERQRLAA
  VVSRIDAYEVVESSSDEVDKLLKEFLHLDLTAPIPGASPEETRQLLLEGSLRMKEGKDSK
  MDVYCFLFTDLLLVTKAVKKAERTRVIRPPLLVDKIVCRELRDPGSFLLIYLNEFHSAVG
  AYTFQASGQALCRGWVDTIYNAQNQLQQLRAQEPPGSQQPLQSLEEEEDEQEEEEEEEEE
  EEEGEDSGTSAASSPTIMRKSSGSPDSQHCASDGSTETLAMVVVEPGDTLSSPEFDSGPF
  SSQSDETSLSTTASSATPTSELLPLGPVDGRSCSMDSAYGTLSPTSLQDFVAPGPMAELV
  PRAPESPRVPSPPPSPRLRRRTPVQLLSCPPHLLKSKSEASLLQLLAGAGTHGTPSAPSR
  SLSELCLAVPAPGIRTQGSPQEAGPSWDCRGAPSPGSGPGLVGCLAGEPAGSHRKRCGDL
  PSGASPRVQPEPPPGVSAQHRKLTLAQLYRIRTTLLLNSTLTASEV
• Function: Functions as a guanine exchange factor (GEF) for RAB26 and thus regulates autophagy of synaptic vesicles in axon terminal of motoneurons. Involved in the control of neuronal cell differentiation. Plays a role in angiogenesis through regulation of endothelial cells chemotaxis. Affects also the migration, adhesion, and matrix/bone degradation in macrophages and osteoclasts.
• Tissue Specificity: Predominantly expressed in the peripheral nervous system and brain. Highest expression is observed in heart, lung, kidney, testis and moderate expression is present in spleen, pancreas, skeletal muscle, ovary and liver. Weakly expressed in glioblastoma (GBM) cell lines.
• KEGG Pathway: Pathways in cancer (hsa05200)
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  RHOA GTPase cycle (R-HSA-8980692)
  RND3 GTPase cycle (R-HSA-9696264)
  RND1 GTPase cycle (R-HSA-9696273)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuromuscular disease	DISQTIJZ	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Charcot-Marie-Tooth disease recessive intermediate C	DISDOX5Z	Strong	Autosomal recessive	[4]
Dementia	DISXL1WY	Strong	Genetic Variation	[5]
Glioma	DIS5RPEH	Strong	Altered Expression	[6]
Motor neurone disease	DISUHWUI	Strong	Genetic Variation	[7]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[8]
Neuronopathy, distal hereditary motor, autosomal recessive 4	DISZ3Y3Y	Strong	Autosomal recessive	[7]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	moderate	Biomarker	[10]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[10]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[11]
Distal hereditary motor neuropathy	DISGS2ID	Limited	Biomarker	[7]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Pleckstrin homology domain-containing family G member 5 (PLEKHG5) affects the response to substance of Temozolomide.	[24]
DTI-015	DMXZRW0	Approved	Pleckstrin homology domain-containing family G member 5 (PLEKHG5) affects the response to substance of DTI-015.	[24]

5 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 Pleckstrin homology domain-containing family G member 5 (PLEKHG5).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Pleckstrin homology domain-containing family G member 5 (PLEKHG5).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Pleckstrin homology domain-containing family G member 5 (PLEKHG5).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Pleckstrin homology domain-containing family G member 5 (PLEKHG5).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Pleckstrin homology domain-containing family G member 5 (PLEKHG5).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pleckstrin homology domain-containing family G member 5 (PLEKHG5).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pleckstrin homology domain-containing family G member 5 (PLEKHG5).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pleckstrin homology domain-containing family G member 5 (PLEKHG5).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Pleckstrin homology domain-containing family G member 5 (PLEKHG5).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Pleckstrin homology domain-containing family G member 5 (PLEKHG5).	[18]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Pleckstrin homology domain-containing family G member 5 (PLEKHG5).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Pleckstrin homology domain-containing family G member 5 (PLEKHG5).	[20]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] NRP-1 interacts with GIPC1 and SYX to activate p38 MAPK signaling and cancer stem cell survival.Mol Carcinog. 2019 Apr;58(4):488-499. doi: 10.1002/mc.22943. Epub 2018 Dec 21.
• [3] Impact of working situation on mental and physical health for informal caregivers of older people with Alzheimer's disease in Italy. Results from the UP-TECH longitudinal study.Aging Ment Health. 2021 Jan;25(1):22-31. doi: 10.1080/13607863.2019.1667295. Epub 2019 Sep 23.
• [4] PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease. Hum Mol Genet. 2013 Oct 15;22(20):4224-32. doi: 10.1093/hmg/ddt274. Epub 2013 Jun 17.
• [5] Using sensor-based technology for safety and independence - the experiences of people with dementia and their families.Scand J Caring Sci. 2020 Sep;34(3):648-657. doi: 10.1111/scs.12766. Epub 2019 Oct 15.
• [6] PLEKHG5 is a novel prognostic biomarker in glioma patients.Int J Clin Oncol. 2019 Nov;24(11):1350-1358. doi: 10.1007/s10147-019-01503-0. Epub 2019 Jul 15.
• [7] The nuclear factor kappaB-activator gene PLEKHG5 is mutated in a form of autosomal recessive lower motor neuron disease with childhood onset. Am J Hum Genet. 2007 Jul;81(1):67-76. doi: 10.1086/518900. Epub 2007 May 16.
• [8] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [9] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [10] The gene for a new brain specific RhoA exchange factor maps to the highly unstable chromosomal region 1p36.2-1p36.3.Oncogene. 2001 Nov 1;20(50):7307-17. doi: 10.1038/sj.onc.1204921.
• [11] Landscape of the relationship between type 2 diabetes and coronary heart disease through an integrated gene network analysis.Gene. 2014 Apr 10;539(1):30-6. doi: 10.1016/j.gene.2014.02.001. Epub 2014 Feb 5.
• [12] 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.
• [13] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [14] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [19] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [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.
• [23] 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.
• [24] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.