Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIFSVI8)

• DOT Name: Serine/threonine-protein kinase D2 (PRKD2)
• Synonyms: EC 2.7.11.13; nPKC-D2
• Gene Name: PRKD2
• Related Disease:
  Gastric neoplasm
  Lung adenocarcinoma
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Adenocarcinoma
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Carcinoid tumor
  Glioblastoma multiforme
  Glioma
  Hyperinsulinemia
  Metabolic disorder
  Multiple sclerosis
  Myeloid leukaemia
  Nasopharyngeal carcinoma
  Neoplasm
  Polycystic ovarian syndrome
  Primary sclerosing cholangitis
  Sclerosing cholangitis
  Triple negative breast cancer
  Type-1 diabetes
  Polycystic kidney disease
  Small lymphocytic lymphoma
• UniProt ID: KPCD2_HUMAN
• PDB ID: 2COA; 3BGM; 4NNX; 4NNY
• EC Number: 2.7.11.13
• Pfam ID: PF00130 ; PF00169 ; PF00069
• Sequence:
  MATAPSYPAGLPGSPGPGSPPPPGGLELQSPPPLLPQIPAPGSGVSFHIQIGLTREFVLL
  PAASELAHVKQLACSIVDQKFPECGFYGLYDKILLFKHDPTSANLLQLVRSSGDIQEGDL
  VEVVLSASATFEDFQIRPHALTVHSYRAPAFCDHCGEMLFGLVRQGLKCDGCGLNYHKRC
  AFSIPNNCSGARKRRLSSTSLASGHSVRLGTSESLPCTAEELSRSTTELLPRRPPSSSSS
  SSASSYTGRPIELDKMLLSKVKVPHTFLIHSYTRPTVCQACKKLLKGLFRQGLQCKDCKF
  NCHKRCATRVPNDCLGEALINGDVPMEEATDFSEADKSALMDESEDSGVIPGSHSENALH
  ASEEEEGEGGKAQSSLGYIPLMRVVQSVRHTTRKSSTTLREGWVVHYSNKDTLRKRHYWR
  LDCKCITLFQNNTTNRYYKEIPLSEILTVESAQNFSLVPPGTNPHCFEIVTANATYFVGE
  MPGGTPGGPSGQGAEAARGWETAIRQALMPVILQDAPSAPGHAPHRQASLSISVSNSQIQ
  ENVDIATVYQIFPDEVLGSGQFGVVYGGKHRKTGRDVAVKVIDKLRFPTKQESQLRNEVA
  ILQSLRHPGIVNLECMFETPEKVFVVMEKLHGDMLEMILSSEKGRLPERLTKFLITQILV
  ALRHLHFKNIVHCDLKPENVLLASADPFPQVKLCDFGFARIIGEKSFRRSVVGTPAYLAP
  EVLLNQGYNRSLDMWSVGVIMYVSLSGTFPFNEDEDINDQIQNAAFMYPASPWSHISAGA
  IDLINNLLQVKMRKRYSVDKSLSHPWLQEYQTWLDLRELEGKMGERYITHESDDARWEQF
  AAEHPLPGSGLPTDRDLGGACPPQDHDMQGLAERISVL
• Function: Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of cell proliferation via MAPK1/3 (ERK1/2) signaling, oxidative stress-induced NF-kappa-B activation, inhibition of HDAC7 transcriptional repression, signaling downstream of T-cell antigen receptor (TCR) and cytokine production, and plays a role in Golgi membrane trafficking, angiogenesis, secretory granule release and cell adhesion. May potentiate mitogenesis induced by the neuropeptide bombesin by mediating an increase in the duration of MAPK1/3 (ERK1/2) signaling, which leads to accumulation of immediate-early gene products including FOS that stimulate cell cycle progression. In response to oxidative stress, is phosphorylated at Tyr-438 and Tyr-717 by ABL1, which leads to the activation of PRKD2 without increasing its catalytic activity, and mediates activation of NF-kappa-B. In response to the activation of the gastrin receptor CCKBR, is phosphorylated at Ser-244 by CSNK1D and CSNK1E, translocates to the nucleus, phosphorylates HDAC7, leading to nuclear export of HDAC7 and inhibition of HDAC7 transcriptional repression of NR4A1/NUR77. Upon TCR stimulation, is activated independently of ZAP70, translocates from the cytoplasm to the nucleus and is required for interleukin-2 (IL2) promoter up-regulation. During adaptive immune responses, is required in peripheral T-lymphocytes for the production of the effector cytokines IL2 and IFNG after TCR engagement and for optimal induction of antibody responses to antigens. In epithelial cells stimulated with lysophosphatidic acid (LPA), is activated through a PKC-dependent pathway and mediates LPA-stimulated interleukin-8 (IL8) secretion via a NF-kappa-B-dependent pathway. During TCR-induced T-cell activation, interacts with and is activated by the tyrosine kinase LCK, which results in the activation of the NFAT transcription factors. In the trans-Golgi network (TGN), regulates the fission of transport vesicles that are on their way to the plasma membrane and in polarized cells is involved in the transport of proteins from the TGN to the basolateral membrane. Plays an important role in endothelial cell proliferation and migration prior to angiogenesis, partly through modulation of the expression of KDR/VEGFR2 and FGFR1, two key growth factor receptors involved in angiogenesis. In secretory pathway, is required for the release of chromogranin-A (CHGA)-containing secretory granules from the TGN. Downstream of PRKCA, plays important roles in angiotensin-2-induced monocyte adhesion to endothelial cells. Plays a regulatory role in angiogenesis and tumor growth by phosphorylating a downstream mediator CIB1 isoform 2, resulting in vascular endothelial growth factor A (VEGFA) secretion.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Aldosterone synthesis and secretion (hsa04925)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric neoplasm	DISOKN4Y	Definitive	Posttranslational Modification	[1]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[2]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Carcinoid tumor	DISMNRDC	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Glioma	DIS5RPEH	Strong	Biomarker	[9]
Hyperinsulinemia	DISIDWT6	Strong	Altered Expression	[10]
Metabolic disorder	DIS71G5H	Strong	Altered Expression	[10]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[11]
Myeloid leukaemia	DISMN944	Strong	Altered Expression	[12]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[13]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[14]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[15]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Genetic Variation	[16]
Sclerosing cholangitis	DIS7GZNB	Strong	Genetic Variation	[17]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[7]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[18]
Polycystic kidney disease	DISWS3UY	moderate	Biomarker	[19]
Small lymphocytic lymphoma	DIS30POX	Limited	Genetic Variation	[20]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Piperazinyl methyl quinazolinone derivative 2	DM913KS	Patented	Serine/threonine-protein kinase D2 (PRKD2) affects the response to substance of Piperazinyl methyl quinazolinone derivative 2.	[35]

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 Serine/threonine-protein kinase D2 (PRKD2).	[21]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the phosphorylation of Serine/threonine-protein kinase D2 (PRKD2).	[31]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Serine/threonine-protein kinase D2 (PRKD2).	[34]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Serine/threonine-protein kinase D2 (PRKD2).	[34]

12 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 Serine/threonine-protein kinase D2 (PRKD2).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Serine/threonine-protein kinase D2 (PRKD2).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Serine/threonine-protein kinase D2 (PRKD2).	[24]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Serine/threonine-protein kinase D2 (PRKD2).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Serine/threonine-protein kinase D2 (PRKD2).	[26]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine/threonine-protein kinase D2 (PRKD2).	[27]
Selenium	DM25CGV	Approved	Selenium increases the expression of Serine/threonine-protein kinase D2 (PRKD2).	[28]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Serine/threonine-protein kinase D2 (PRKD2).	[29]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Serine/threonine-protein kinase D2 (PRKD2).	[29]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine/threonine-protein kinase D2 (PRKD2).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Serine/threonine-protein kinase D2 (PRKD2).	[32]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Serine/threonine-protein kinase D2 (PRKD2).	[33]

References

• [1] Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2.EMBO J. 2007 Nov 14;26(22):4619-33. doi: 10.1038/sj.emboj.7601891. Epub 2007 Oct 25.
• [2] High PKD2 predicts poor prognosis in lung adenocarcinoma via promoting Epithelial-mesenchymal Transition.Sci Rep. 2019 Feb 4;9(1):1324. doi: 10.1038/s41598-018-37285-0.
• [3] PRKD2 Promotes Progression and Chemoresistance of AML via Regulating Notch1 Pathway.Onco Targets Ther. 2019 Dec 12;12:10931-10941. doi: 10.2147/OTT.S233234. eCollection 2019.
• [4] Lack of PRKD2 and PRKD3 kinase domain somatic mutations in PRKD1 wild-type classic polymorphous low-grade adenocarcinomas of the salivary gland.Histopathology. 2016 Jun;68(7):1055-62. doi: 10.1111/his.12883. Epub 2016 Jan 4.
• [5] Protein kinase D2 regulates migration and invasion of U87MG glioblastoma cells in vitro.Exp Cell Res. 2013 Aug 1;319(13):2037-2048. doi: 10.1016/j.yexcr.2013.03.029. Epub 2013 Apr 4.
• [6] Protein kinase D2: a versatile player in cancer biology.Oncogene. 2018 Mar;37(10):1263-1278. doi: 10.1038/s41388-017-0052-8. Epub 2017 Dec 20.
• [7] The Role and Mechanism of CRT0066101 as an Effective Drug for Treatment of Triple-Negative Breast Cancer.Cell Physiol Biochem. 2019;52(3):382-396. doi: 10.33594/000000027. Epub 2019 Mar 8.
• [8] Overexpression of wild-type PKD2 leads to increased proliferation and invasion of BON endocrine cells.Biochem Biophys Res Commun. 2006 Sep 29;348(3):945-9. doi: 10.1016/j.bbrc.2006.07.142. Epub 2006 Jul 31.
• [9] Protein kinase D2 promotes the proliferation of glioma cells by regulating Golgi phosphoprotein 3.Cancer Lett. 2014 Dec 1;355(1):121-9. doi: 10.1016/j.canlet.2014.09.008. Epub 2014 Sep 16.
• [10] Deficiency of PRKD2 triggers hyperinsulinemia and metabolic disorders.Nat Commun. 2018 May 22;9(1):2015. doi: 10.1038/s41467-018-04352-z.
• [11] Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
• [12] Protein kinase D2 mediates activation of nuclear factor kappaB by Bcr-Abl in Bcr-Abl+ human myeloid leukemia cells.Cancer Res. 2004 Dec 15;64(24):8939-44. doi: 10.1158/0008-5472.CAN-04-0981.
• [13] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [14] Genomic analysis of recurrences and high-grade forms of polymorphous adenocarcinoma.Histopathology. 2019 Aug;75(2):193-201. doi: 10.1111/his.13854. Epub 2019 Jun 18.
• [15] 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.
• [16] Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.Nat Genet. 2013 Jun;45(6):670-5. doi: 10.1038/ng.2616. Epub 2013 Apr 21.
• [17] Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):269-273. doi: 10.1038/ng.3745. Epub 2016 Dec 19.
• [18] Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.Nat Genet. 2015 Apr;47(4):381-6. doi: 10.1038/ng.3245. Epub 2015 Mar 9.
• [19] Polycystic Kidney Disease: Lessons Learned from Caenorhabditis elegans Mating Behavior.Curr Biol. 2015 Dec 21;25(24):R1168-70. doi: 10.1016/j.cub.2015.09.061.
• [20] A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia.Nat Genet. 2008 Oct;40(10):1204-10. doi: 10.1038/ng.219. Epub 2008 Aug 31.
• [21] 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.
• [22] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [23] 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.
• [24] 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.
• [25] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [26] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [27] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [28] 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.
• [29] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [30] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [31] Protein kinase d as a potential chemotherapeutic target for colorectal cancer. Mol Cancer Ther. 2014 May;13(5):1130-41. doi: 10.1158/1535-7163.MCT-13-0880. Epub 2014 Mar 14.
• [32] 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.
• [33] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [34] 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.
• [35] Targeting PKD2 aggravates ferritinophagy-mediated ferroptosis via promoting autophagosome-lysosome fusion and enhances efficacy of carboplatin in lung adenocarcinoma. Chem Biol Interact. 2024 Jan 5;387:110794. doi: 10.1016/j.cbi.2023.110794. Epub 2023 Nov 10.