Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3LPG1R)

• DOT Name: Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C)
• Synonyms: PIP5K1gamma; PtdIns(4)P-5-kinase 1 gamma; EC 2.7.1.68; Type I phosphatidylinositol 4-phosphate 5-kinase gamma
• Gene Name: PIP5K1C
• Related Disease:
  Rabies
  Breast cancer
  Breast carcinoma
  Familial adenomatous polyposis 2
  Invasive ductal breast carcinoma
  Lethal congenital contracture syndrome 3
  Complex neurodevelopmental disorder
• UniProt ID: PI51C_HUMAN
• PDB ID: 2G35; 3H1Z; 3H85
• EC Number: 2.7.1.68
• Pfam ID: PF01504
• Sequence:
  MELEVPDEAESAEAGAVPSEAAWAAESGAAAGLAQKKAAPTEVLSMTAQPGPGHGKKLGH
  RGVDASGETTYKKTTSSTLKGAIQLGIGYTVGHLSSKPERDVLMQDFYVVESIFFPSEGS
  NLTPAHHFQDFRFKTYAPVAFRYFRELFGIRPDDYLYSLCNEPLIELSNPGASGSLFYVT
  SDDEFIIKTVMHKEAEFLQKLLPGYYMNLNQNPRTLLPKFYGLYCVQSGGKNIRVVVMNN
  ILPRVVKMHLKFDLKGSTYKRRASKKEKEKSFPTYKDLDFMQDMPEGLLLDADTFSALVK
  TLQRDCLVLESFKIMDYSLLLGVHNIDQHERERQAQGAQSTSDEKRPVGQKALYSTAMES
  IQGGAARGEAIESDDTMGGIPAVNGRGERLLLHIGIIDILQSYRFIKKLEHTWKALVHDG
  DTVSVHRPSFYAERFFKFMSNTVFRKNSSLKSSPSKKGRGGALLAVKPLGPTAAFSASQI
  PSEREEAQYDLRGARSYPTLEDEGRPDLLPCTPPSFEEATTASIATTLSSTSLSIPERSP
  SETSEQPRYRRRTQSSGQDGRPQEEPPAEEDLQQITVQVEPACSVEIVVPKEEDAGVEAS
  PAGASAAVEVETASQASDEEGAPASQASDEEDAPATDIYFPTDERSWVYSPLHYSAQAPP
  ASDGESDT
• Function: Catalyzes the phosphorylation of phosphatidylinositol 4-phosphate (PtdIns(4)P/PI4P) to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2/PIP2), a lipid second messenger that regulates several cellular processes such as signal transduction, vesicle trafficking, actin cytoskeleton dynamics, cell adhesion, and cell motility. PtdIns(4,5)P2 can directly act as a second messenger or can be utilized as a precursor to generate other second messengers: inositol 1,4,5-trisphosphate (IP3), diacylglycerol (DAG) or phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3/PIP3) (Probable). PIP5K1A-mediated phosphorylation of PtdIns(4)P is the predominant pathway for PtdIns(4,5)P2 synthesis. Together with PIP5K1A, is required for phagocytosis, both enzymes regulating different types of actin remodeling at sequential steps. Promotes particle attachment by generating the pool of PtdIns(4,5)P2 that induces controlled actin depolymerization to facilitate Fc-gamma-R clustering. Mediates RAC1-dependent reorganization of actin filaments. Required for synaptic vesicle transport. Controls the plasma membrane pool of PtdIns(4,5)P2 implicated in synaptic vesicle endocytosis and exocytosis. Plays a role in endocytosis mediated by clathrin and AP-2 (adaptor protein complex 2). Required for clathrin-coated pits assembly at the synapse. Participates in cell junction assembly. Modulates adherens junctions formation by facilitating CDH1/cadherin trafficking. Required for focal adhesion dynamics. Modulates the targeting of talins (TLN1 and TLN2) to the plasma membrane and their efficient assembly into focal adhesions. Regulates the interaction between talins (TLN1 and TLN2) and beta-integrins. Required for uropodium formation and retraction of the cell rear during directed migration. Has a role in growth factor-stimulated directional cell migration and adhesion. Required for talin assembly into nascent adhesions forming at the leading edge toward the direction of the growth factor. Negative regulator of T-cell activation and adhesion. Negatively regulates integrin alpha-L/beta-2 (LFA-1) polarization and adhesion induced by T-cell receptor. Together with PIP5K1A has a role during embryogenesis and together with PIP5K1B may have a role immediately after birth.
• Tissue Specificity: .Isoform 1 is strongly expressed in brain and also detected in heart and lung.; [Isoform 2]: Isoform 2 is strongly expressed in pancreas and liver and in lesser quantities in brain, heart, lung and kidney.; [Isoform 3]: Isoform 3 is detected in large amounts in heart and large intestine, is also present in lung, pancreas and thyroid, and to a lesser extent in brain, stomach and kidney.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
  Phospholipase D sig.ling pathway (hsa04072)
  Endocytosis (hsa04144)
  Focal adhesion (hsa04510)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Regulation of actin cytoskeleton (hsa04810)
  Yersinia infection (hsa05135)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion (R-HSA-399955)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
• BioCyc Pathway: MetaCyc:HS02710-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rabies	DISSC4V5	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Familial adenomatous polyposis 2	DIS62W3Y	Strong	Altered Expression	[3]
Invasive ductal breast carcinoma	DIS43J58	Strong	Biomarker	[2]
Lethal congenital contracture syndrome 3	DISU931I	Strong	Autosomal recessive	[4]
Complex neurodevelopmental disorder	DISB9AFI	Moderate	Autosomal dominant	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Deoxycholic acid	DM3GYAL	Approved	Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C) decreases the response to substance of Deoxycholic acid.	[14]

3 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 Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C).	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C).	[12]

6 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 Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C).	[8]
Clodronate	DM9Y6X7	Approved	Clodronate affects the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C).	[13]

References

• [1] Kinome-Wide RNA Interference Screening Identifies Mitogen-Activated Protein Kinases and Phosphatidylinositol Metabolism as Key Factors for Rabies Virus Infection.mSphere. 2019 May 22;4(3):e00047-19. doi: 10.1128/mSphere.00047-19.
• [2] The phosphorylation status of PIP5K1C at serine 448 can be predictive for invasive ductal carcinoma of the breast.Oncotarget. 2018 Nov 20;9(91):36358-36370. doi: 10.18632/oncotarget.26357. eCollection 2018 Nov 20.
• [3] Gene expression profiles of immune-regulatory genes in whole blood of cattle with a subclinical infection of Mycobacterium avium subsp. paratuberculosis.PLoS One. 2018 Apr 26;13(4):e0196502. doi: 10.1371/journal.pone.0196502. eCollection 2018.
• [4] Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI gamma of the phophatidylinsitol pathway. Am J Hum Genet. 2007 Sep;81(3):530-9. doi: 10.1086/520771. Epub 2007 Jul 24.
• [5] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [6] 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.
• [7] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [8] 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.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [14] Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. Carcinogenesis. 2002 Dec;23(12):2063-80. doi: 10.1093/carcin/23.12.2063.