General Information of Drug Off-Target (DOT) (ID: OTXB1OUI)

DOT Name PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2)
Synonyms EC 3.1.3.16; PH domain leucine-rich repeat-containing protein phosphatase-like; PHLPP-like
Gene Name PHLPP2
Related Disease
Melanoma ( )
Acute myelogenous leukaemia ( )
Acute myocardial infarction ( )
Bladder cancer ( )
Breast carcinoma ( )
Colon cancer ( )
Colon carcinoma ( )
Esophageal squamous cell carcinoma ( )
Fatty liver disease ( )
Glioma ( )
Hepatocellular carcinoma ( )
Hypopharyngeal squamous cell carcinoma ( )
Lung adenocarcinoma ( )
Myocardial infarction ( )
Non-alcoholic fatty liver disease ( )
Pneumonia ( )
Pneumonitis ( )
Prostate carcinoma ( )
Squamous cell carcinoma ( )
Urinary bladder cancer ( )
Urinary bladder neoplasm ( )
Chronic obstructive pulmonary disease ( )
Prostate cancer ( )
Advanced cancer ( )
Breast cancer ( )
Non-small-cell lung cancer ( )
UniProt ID
PHLP2_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
EC Number
3.1.3.16
Pfam ID
PF00560 ; PF13516 ; PF13855 ; PF00481
Sequence
MKRNGSRNCLNRRSRFGSRERDWLREDVKRGCVYLYGADTTTATTTTTTSSSSSSSSSSS
DLHLVLCTVETPASEICAGEGRESLYLQLHGDLVRRLEPTERPLQIVYDYLSRLGFDDPV
RIQEEATNPDLGCMIRFYGEKPCHMDRLDRILLSGIYNVRKGKTQLHKWAERLVVLCGTC
LIVSSVKDCQTGKMHILPLVGGKIEEVKRRQYSLAFSSAGAQAQTYHVSFETLAEYQRWQ
RQASKVVSQRISTVDLSCYSLEEVPEHLFYSQDITYLNLRHNFMQLERPGGLDTLYKFSQ
LKGLNLSHNKLGLFPILLCEISTLTELNLSCNGFHDLPSQIGNLLNLQTLCLDGNFLTTL
PEELGNLQQLSSLGISFNNFSQIPEVYEKLTMLDRVVMAGNCLEVLNLGVLNRMNHIKHV
DLRMNHLKTMVIENLEGNKHITHVDLRDNRLTDLDLSSLCSLEQLHCGRNQLRELTLSGF
SLRTLYASSNRLTAVNVYPVPSLLTFLDLSRNLLECVPDWACEAKKIEVLDVSYNLLTEV
PVRILSSLSLRKLMLGHNHVQNLPTLVEHIPLEVLDLQHNALTRLPDTLFSKALNLRYLN
ASANSLESLPSACTGEESLSMLQLLYLTNNLLTDQCIPVLVGHLHLRILHLANNQLQTFP
ASKLNKLEQLEELNLSGNKLKTIPTTIANCKRLHTLVAHSNNISIFPEILQLPQIQFVDL
SCNDLTEILIPEALPATLQDLDLTGNTNLVLEHKTLDIFSHITTLKIDQKPLPTTDSTVT
STFWSHGLAEMAGQRNKLCVSALAMDSFAEGVGAVYGMFDGDRNEELPRLLQCTMADVLL
EEVQQSTNDTVFMANTFLVSHRKLGMAGQKLGSSALLCYIRPDTADPASSFSLTVANVGT
CQAVLCRGGKPVPLSKVFSLEQDPEEAQRVKDQKAIITEDNKVNGVTCCTRMLGCTYLYP
WILPKPHISSTPLTIQDELLILGNKALWEHLSYTEAVNAVRHVQDPLAAAKKLCTLAQSY
GCQDNVGAMVVYLNIGEEGCTCEMNGLTLPGPVGFASTTTIKDAPKPATPSSSSGIASEF
SSEMSTSEVSSEVGSTASDEHNAGGLDTALLPRPERRCSLHPTPTSGLFQRQPSSATFSS
NQSDNGLDSDDDQPVEGVITNGSKVEVEVDIHCCRGRDLENSPPLIESSPTLCSEEHARG
SCFGIRRQNSVNSGMLLPMSKDRMELQKSPSTSCLYGKKLSNGSIVPLEDSLNLIEVATE
VPKRKTGYFAAPTQMEPEDQFVVPHDLEEEVKEQMKQHQDSRLEPEPHEEDRTEPPEEFD
TAL
Function
Protein phosphatase involved in regulation of Akt and PKC signaling. Mediates dephosphorylation in the C-terminal domain hydrophobic motif of members of the AGC Ser/Thr protein kinase family; specifically acts on 'Ser-473' of AKT1, 'Ser-660' of PRKCB isoform beta-II and 'Ser-657' of PRKCA. Akt regulates the balance between cell survival and apoptosis through a cascade that primarily alters the function of transcription factors that regulate pro- and antiapoptotic genes. Dephosphorylation of 'Ser-473' of Akt triggers apoptosis and decreases cell proliferation. Also controls the phosphorylation of AKT3. Dephosphorylates STK4 on 'Thr-387' leading to STK4 activation and apoptosis. Dephosphorylates RPS6KB1 and is involved in regulation of cap-dependent translation. Inhibits cancer cell proliferation and may act as a tumor suppressor. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation. Dephosphorylates RAF1 inhibiting its kinase activity.
Tissue Specificity
In colorectal cancer tissue, expression is highest in the surface epithelium of normal colonic mucosa adjacent to the cancer tissue but is largely excluded from the crypt bases. Expression is lost or significantly decreased in 80% of tested tumors (at protein level).
KEGG Pathway
PI3K-Akt sig.ling pathway (hsa04151 )
Reactome Pathway
Negative regulation of the PI3K/AKT network (R-HSA-199418 )

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Melanoma DIS1RRCY Definitive Altered Expression [1]
Acute myelogenous leukaemia DISCSPTN Strong Altered Expression [2]
Acute myocardial infarction DISE3HTG Strong Biomarker [3]
Bladder cancer DISUHNM0 Strong Biomarker [4]
Breast carcinoma DIS2UE88 Strong Biomarker [5]
Colon cancer DISVC52G Strong Altered Expression [6]
Colon carcinoma DISJYKUO Strong Altered Expression [6]
Esophageal squamous cell carcinoma DIS5N2GV Strong Altered Expression [7]
Fatty liver disease DIS485QZ Strong Biomarker [8]
Glioma DIS5RPEH Strong Biomarker [9]
Hepatocellular carcinoma DIS0J828 Strong Biomarker [10]
Hypopharyngeal squamous cell carcinoma DISDDD65 Strong Altered Expression [11]
Lung adenocarcinoma DISD51WR Strong Altered Expression [12]
Myocardial infarction DIS655KI Strong Biomarker [3]
Non-alcoholic fatty liver disease DISDG1NL Strong Altered Expression [8]
Pneumonia DIS8EF3M Strong Biomarker [13]
Pneumonitis DIS88E0K Strong Biomarker [13]
Prostate carcinoma DISMJPLE Strong Biomarker [14]
Squamous cell carcinoma DISQVIFL Strong Altered Expression [15]
Urinary bladder cancer DISDV4T7 Strong Biomarker [4]
Urinary bladder neoplasm DIS7HACE Strong Biomarker [4]
Chronic obstructive pulmonary disease DISQCIRF moderate Altered Expression [16]
Prostate cancer DISF190Y moderate Biomarker [14]
Advanced cancer DISAT1Z9 Limited Biomarker [17]
Breast cancer DIS7DPX1 Limited Biomarker [5]
Non-small-cell lung cancer DIS5Y6R9 Limited Biomarker [15]
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⏷ Show the Full List of 26 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
10 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the expression of PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2). [18]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2). [19]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2). [20]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2). [21]
Estradiol DMUNTE3 Approved Estradiol increases the expression of PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2). [22]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2). [23]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 increases the expression of PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2). [24]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2). [25]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2). [26]
Acetaldehyde DMJFKG4 Investigative Acetaldehyde decreases the expression of PH domain leucine-rich repeat-containing protein phosphatase 2 (PHLPP2). [27]
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⏷ Show the Full List of 10 Drug(s)

References

1 PHLPP1 mediates melanoma metastasis suppression through repressing AKT2 activation.Oncogene. 2018 Apr;37(17):2225-2236. doi: 10.1038/s41388-017-0061-7. Epub 2018 Feb 2.
2 Transcription factor C/EBP- induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17-92 cluster in differentiating AML cells.Cell Death Differ. 2016 Jul;23(7):1232-42. doi: 10.1038/cdd.2016.1. Epub 2016 Feb 12.
3 PHLPP2 downregulation protects cardiomyocytes against hypoxia-induced injury through reinforcing Nrf2/ARE antioxidant signaling.Chem Biol Interact. 2019 Dec 1;314:108848. doi: 10.1016/j.cbi.2019.108848. Epub 2019 Oct 11.
4 LncRNA MBNL1-AS1 represses cell proliferation and enhances cell apoptosis via targeting miR-135a-5p/PHLPP2/FOXO1 axis in bladder cancer.Cancer Med. 2020 Jan;9(2):724-736. doi: 10.1002/cam4.2684. Epub 2019 Nov 25.
5 CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial-Mesenchymal Plasticity in Breast Cancer.Cancer Res. 2019 Jan 1;79(1):47-60. doi: 10.1158/0008-5472.CAN-18-1742. Epub 2018 Nov 1.
6 Identification and development of long non-coding RNA-associated regulatory network in colorectal cancer.J Cell Mol Med. 2019 Aug;23(8):5200-5210. doi: 10.1111/jcmm.14395. Epub 2019 May 29.
7 MiR-141-3p is upregulated in esophageal squamous cell carcinoma and targets pleckstrin homology domain leucine-rich repeat protein phosphatase-2, a negative regulator of the PI3K/AKT pathway.Biochem Biophys Res Commun. 2018 Jun 22;501(2):507-513. doi: 10.1016/j.bbrc.2018.05.025. Epub 2018 May 16.
8 Degradation of PHLPP2 by KCTD17, via a Glucagon-Dependent Pathway, Promotes Hepatic Steatosis.Gastroenterology. 2017 Dec;153(6):1568-1580.e10. doi: 10.1053/j.gastro.2017.08.039. Epub 2017 Aug 30.
9 miR-372 regulates glioma cell proliferation and invasion by directly targeting PHLPP2.J Cell Biochem. 2015 Feb;116(2):225-32. doi: 10.1002/jcb.24949.
10 Berberine induced modulation of PHLPP2-Akt-MST1 kinase signaling is coupled with mitochondrial impairment and hepatoma cell death.Toxicol Appl Pharmacol. 2018 May 15;347:92-103. doi: 10.1016/j.taap.2018.03.033. Epub 2018 Apr 4.
11 Aberrant expression of PHLPP1 and PHLPP2 correlates with poor prognosis in patients with hypopharyngeal squamous cell carcinoma.PLoS One. 2015 Mar 20;10(3):e0119405. doi: 10.1371/journal.pone.0119405. eCollection 2015.
12 High PHLPP1 expression levels predicts longer time of acquired resistance to EGFR tyrosine kinase inhibitors in patients with lung adenocarcinoma.Oncotarget. 2017 Aug 1;8(35):59000-59007. doi: 10.18632/oncotarget.19777. eCollection 2017 Aug 29.
13 PHLPP2 Downregulation Contributes to Lung Carcinogenesis Following B[a]P/B[a]PDE Exposure.Clin Cancer Res. 2015 Aug 15;21(16):3783-93. doi: 10.1158/1078-0432.CCR-14-2829. Epub 2015 May 14.
14 The PHLPP2 phosphatase is a druggable driver of prostate cancer progression.J Cell Biol. 2019 Jun 3;218(6):1943-1957. doi: 10.1083/jcb.201902048. Epub 2019 May 15.
15 PHLPP2 as a novel metastatic and prognostic biomarker in non-small cell lung cancer patients.Thorac Cancer. 2019 Nov;10(11):2124-2132. doi: 10.1111/1759-7714.13196. Epub 2019 Sep 30.
16 Role of miR-195 in cigarette smoke-induced chronic obstructive pulmonary disease.Int Immunopharmacol. 2018 Feb;55:49-54. doi: 10.1016/j.intimp.2017.11.030. Epub 2017 Dec 22.
17 PHLPPing through history: a decade in the life of PHLPP phosphatases.Biochem Soc Trans. 2016 Dec 15;44(6):1675-1682. doi: 10.1042/BST20160170.
18 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
19 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.
20 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.
21 Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
22 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.
23 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
24 Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
25 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.
26 Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
27 In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.