Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMGR6I6)

• DOT Name: Pleckstrin homology domain-containing family G member 2 (PLEKHG2)
• Synonyms: PH domain-containing family G member 2
• Gene Name: PLEKHG2
• Related Disease:
  Acute lymphocytic leukaemia
  Cerebellar ataxia
  Childhood acute lymphoblastic leukemia
  Leukodystrophy and acquired microcephaly with or without dystonia
  Lung neoplasm
  Lymphoma, non-Hodgkin, familial
  Myeloid leukaemia
  Non-hodgkin lymphoma
  T-cell acute lymphoblastic leukaemia
  Neoplasm
• UniProt ID: PKHG2_HUMAN
• Pfam ID: PF00169 ; PF00621
• Sequence:
  MPEGAQGLSLSKPSPSLGCGRRGEVCDCGTVCETRTAPAAPTMASPRGSGSSTSLSTVGS
  EGDPAPGPTPACSASRPEPLPGPPIRLHLSPVGIPGSARPSRLERVAREIVETERAYVRD
  LRSIVEDYLGPLLDGGVLGLSVEQVGTLFANIEDIYEFSSELLEDLENSSSAGGIAECFV
  QRSEDFDIYTLYCMNYPSSLALLRELSLSPPAALWLQERQAQLRHSLPLQSFLLKPVQRI
  LKYHLLLQELGKHWAEGPGTGGREMVEEAIVSMTAVAWYINDMKRKQEHAARLQEVQRRL
  GGWTGPELSAFGELVLEGAFRGGGGGGPRLRGGERLLFLFSRMLLVAKRRGLEYTYKGHI
  FCCNLSVSESPRDPLGFKVSDLTIPKHRHLLQAKNQEEKRLWIHCLQRLFFENHPASIPA
  KAKQVLLENSLHCAPKSKPVLEPLTPPLGSPRPRDARSFTPGRRNTAPSPGPSVIRRGRR
  QSEPVKDPYVMFPQNAKPGFKHAGSEGELYPPESQPPVSGSAPPEDLEDAGPPTLDPSGT
  SITEEILELLNQRGLRDPGPSTHDIPKFPGDSQVPGDSETLTFQALPSRDSSEEEEEEEE
  GLEMDERGPSPLHVLEGLESSIAAEMPSIPCLTKIPDVPNLPEIPSRCEIPEGSRLPSLS
  DISDVFEMPCLPAIPSVPNTPSLSSTPTLSCDSWLQGPLQEPAEAPATRRELFSGSNPGK
  LGEPPSGGKAGPEEDEEGVSFTDFQPQDVTQHQGFPDELAFRSCSEIRSAWQALEQGQLA
  RPGFPEPLLILEDSDLGGDSGSGKAGAPSSERTASRVRELARLYSERIQQMQRAETRASA
  NAPRRRPRVLAQPQPSPCLPQEQAEPGLLPAFGHVLVCELAFPLTCAQESVPLGPAVWVQ
  AAIPLSKQGGSPDGQGLHVSNLPKQDLPGIHVSAATLLPEQGGSRHVQAPAATPLPKQEG
  PLHLQVPALTTFSDQGHPEIQVPATTPLPEHRSHMVIPAPSTAFCPEQGHCADIHVPTTP
  ALPKEICSDFTVSVTTPVPKQEGHLDSESPTNIPLTKQGGSRDVQGPDPVCSQPIQPLSW
  HGSSLDPQGPGDTLPPLPCHLPDLQIPGTSPLPAHGSHLDHRIPANAPLSLSQELPDTQV
  PATTPLPLPQVLTDIWVQALPTSPKQGSLPDIQGPAAAPPLPEPSLTDTQVQKLTPSLEQ
  KSLIDAHVPAATPLPERGGSLDIQGLSPTPVQTTMVLSKPGGSLASHVARLESSDLTPPH
  SPPPSSRQLLGPNAAALSRYLAASYISQSLARRQGPGGGAPAASRGSWSSAPTSRASSPP
  PQPQPPPPPARRLSYATTVNIHVGGGGRLRPAKAQVRLNHPALLASTQESMGLHRAQGAP
  DAPFHM
• Function: May be a transforming oncogene with exchange activity for CDC42. May be a guanine-nucleotide exchange factor (GEF) for RAC1 and CDC42. Activated by the binding to subunits beta and gamma of the heterotrimeric guanine nucleotide-binding protein (G protein). Involved in the regulation of actin polymerization.
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[1]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[2]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[3]
Leukodystrophy and acquired microcephaly with or without dystonia;	DISZUDAP	Strong	Autosomal recessive	[4]
Lung neoplasm	DISVARNB	Strong	Biomarker	[5]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Biomarker	[3]
Myeloid leukaemia	DISMN944	Strong	Altered Expression	[6]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[3]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[8]

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 Pleckstrin homology domain-containing family G member 2 (PLEKHG2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Pleckstrin homology domain-containing family G member 2 (PLEKHG2).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Pleckstrin homology domain-containing family G member 2 (PLEKHG2).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Pleckstrin homology domain-containing family G member 2 (PLEKHG2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Pleckstrin homology domain-containing family G member 2 (PLEKHG2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Pleckstrin homology domain-containing family G member 2 (PLEKHG2).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Pleckstrin homology domain-containing family G member 2 (PLEKHG2).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Pleckstrin homology domain-containing family G member 2 (PLEKHG2).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Pleckstrin homology domain-containing family G member 2 (PLEKHG2).	[16]

References

• [1] IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951.Leukemia. 2015 Nov;29(11):2154-61. doi: 10.1038/leu.2015.134. Epub 2015 Jun 8.
• [2] Exclusion of stromelysin-1, stromelysin-2, interstitial collagenase and fibronectin genes as the mutant loci in a family with recessive epidermolysis bullosa dystrophica and a form of cerebellar ataxia.Hum Genet. 1992 Jul;89(5):503-7. doi: 10.1007/BF00219174.
• [3] Prolonged versus standard native E. coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951.Haematologica. 2017 Oct;102(10):1727-1738. doi: 10.3324/haematol.2017.165845. Epub 2017 Jul 27.
• [4] The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014 Nov 13;515(7526):216-21. doi: 10.1038/nature13908. Epub 2014 Oct 29.
• [5] Cationic lipid guided short-hairpin RNA interference of annexin A2 attenuates tumor growth and metastasis in a mouse lung cancer stem cell model.J Control Release. 2014 Jun 28;184:67-78. doi: 10.1016/j.jconrel.2014.03.049. Epub 2014 Apr 12.
• [6] Activation of clg, a novel dbl family guanine nucleotide exchange factor gene, by proviral insertion at evi24, a common integration site in B cell and myeloid leukemias.J Biol Chem. 2002 Apr 19;277(16):13463-72. doi: 10.1074/jbc.M110981200. Epub 2002 Feb 11.
• [7] Results of successive EORTC-CLG 58881 and 58951 trials in paediatric T-cell acute lymphoblastic leukaemia (ALL).Br J Haematol. 2019 Sep;186(5):741-753. doi: 10.1111/bjh.15983. Epub 2019 May 24.
• [8] Collagenase-Encapsulated pH-Responsive Nanoscale Coordination Polymers for Tumor Microenvironment Modulation and Enhanced Photodynamic Nanomedicine.ACS Appl Mater Interfaces. 2018 Dec 19;10(50):43493-43502. doi: 10.1021/acsami.8b17684. Epub 2018 Dec 5.
• [9] 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.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [14] 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.
• [15] 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.
• [16] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.