Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIFXW8D)

• DOT Name: PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1)
• Synonyms: EC 3.1.3.16; Pleckstrin homology domain-containing family E member 1; PH domain-containing family E member 1; Suprachiasmatic nucleus circadian oscillatory protein; hSCOP
• Gene Name: PHLPP1
• Related Disease:
  Adenocarcinoma
  Colonic neoplasm
  Colorectal neoplasm
  Diabetic kidney disease
  Hyperglycemia
  Metastatic melanoma
  Adult glioblastoma
  Adult lymphoma
  Advanced cancer
  Astrocytoma
  Cardiac arrest
  Cardiovascular disease
  Colon cancer
  Colon carcinoma
  Dementia
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Glioma
  Gram-negative bacterial infection
  Hepatocellular carcinoma
  Huntington disease
  Hypopharyngeal squamous cell carcinoma
  Intervertebral disc degeneration
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lymphoma
  Non-small-cell lung cancer
  Obesity
  Osteoarthritis
  Pancreatic adenocarcinoma
  Pediatric lymphoma
  Prostate carcinoma
  Prostate neoplasm
  Squamous cell carcinoma
  Coronary atherosclerosis
  Myocardial ischemia
  Non-insulin dependent diabetes
  Prostate cancer
  Small lymphocytic lymphoma
  Castration-resistant prostate carcinoma
  Gallbladder cancer
  Gallbladder carcinoma
  Matthew-Wood syndrome
  Melanoma
  Pancreatic ductal carcinoma
  Tuberous sclerosis
  Type-1/2 diabetes
• UniProt ID: PHLP1_HUMAN
• EC Number: 3.1.3.16
• Pfam ID: PF13516 ; PF13855 ; PF00169 ; PF00481
• Sequence:
  MEPAAAATVQRLPELGREDRASAPAAAAAAAAAAAAAAAALAAAAGGGRSPEPALTPAAP
  SGGNGSGSGAREEAPGEAPPGPLPGRAGGAGRRRRRGAPQPIAGGAAPVPGAGGGANSLL
  LRRGRLKRNLSAAAAAASSSSSSSAAAASHSPGAAGLPASCSASASLCTRSLDRKTLLLK
  HRQTLQLQPSDRDWVRHQLQRGCVHVFDRHMASTYLRPVLCTLDTTAGEVAARLLQLGHK
  GGGVVKVLGQGPGAAAAREPAEPPPEAGPRLAPPEPRDSEVPPARSAPGAFGGPPRAPPA
  DLPLPVGGPGGWSRRASPAPSDSSPGEPFVGGPVSSPRAPRPVVSDTESFSLSPSAESVS
  DRLDPYSSGGGSSSSSEELEADAASAPTGVPGQPRRPGHPAQPLPLPQTASSPQPQQKAP
  RAIDSPGGAVREGSCEEKAAAAVAPGGLQSTPGRSGVTAEKAPPPPPPPTLYVQLHGETT
  RRLEAEEKPLQIQNDYLFQLGFGELWRVQEEGMDSEIGCLIRFYAGKPHSTGSSERIQLS
  GMYNVRKGKMQLPVNRWTRRQVILCGTCLIVSSVKDSLTGKMHVLPLIGGKVEEVKKHQH
  CLAFSSSGPQSQTYYICFDTFTEYLRWLRQVSKVASQRISSVDLSCCSLEHLPANLFYSQ
  DLTHLNLKQNFLRQNPSLPAARGLNELQRFTKLKSLNLSNNHLGDFPLAVCSIPTLAELN
  VSCNALRSVPAAVGVMHNLQTFLLDGNFLQSLPAELENMKQLSYLGLSFNEFTDIPEVLE
  KLTAVDKLCMSGNCVETLRLQALRKMPHIKHVDLRLNVIRKLIADEVDFLQHVTQLDLRD
  NKLGDLDAMIFNNIEVLHCERNQLVTLDICGYFLKALYASSNELVQLDVYPVPNYLSYMD
  VSRNRLENVPEWVCESRKLEVLDIGHNQICELPARLFCNSSLRKLLAGHNQLARLPERLE
  RTSVEVLDVQHNQLLELPPNLLMKADSLRFLNASANKLESLPPATLSEETNSILQELYLT
  NNSLTDKCVPLLTGHPHLKILHMAYNRLQSFPASKMAKLEELEEIDLSGNKLKAIPTTIM
  NCRRMHTVIAHSNCIEVFPEVMQLPEIKCVDLSCNELSEVTLPENLPPKLQELDLTGNPR
  LVLDHKTLELLNNIRCFKIDQPSTGDASGAPAVWSHGYTEASGVKNKLCVAALSVNNFCD
  NREALYGVFDGDRNVEVPYLLQCTMSDILAEELQKTKNEEEYMVNTFIVMQRKLGTAGQK
  LGGAAVLCHIKHDPVDPGGSFTLTSANVGKCQTVLCRNGKPLPLSRSYIMSCEEELKRIK
  QHKAIITEDGKVNGVTESTRILGYTFLHPSVVPRPHVQSVLLTPQDEFFILGSKGLWDSL
  SVEEAVEAVRNVPDALAAAKKLCTLAQSYGCHDSISAVVVQLSVTEDSFCCCELSAGGAV
  PPPSPGIFPPSVNMVIKDRPSDGLGVPSSSSGMASEISSELSTSEMSSEVGSTASDEPPP
  GALSENSPAYPSEQRCMLHPICLSNSFQRQLSSATFSSAFSDNGLDSDDEEPIEGVFTNG
  SRVEVEVDIHCSRAKEKEKQQHLLQVPAEASDEGIVISANEDEPGLPRKADFSAVGTIGR
  RRANGSVAPQERSHNVIEVATDAPLRKPGGYFAAPAQPDPDDQFIIPPELEEEVKEIMKH
  HQEQQQQQQPPPPPQLQPQLPRHYQLDQLPDYYDTPL
• 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 AKT2 and AKT3, 'Ser-660' of PRKCB and 'Ser-657' of PRKCA. Isoform 2 seems to have a major role in regulating Akt signaling in hippocampal neurons. 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 suppression of tumor growth. Dephosphorylation of PRKCA and PRKCB leads to their destabilization and degradation. 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. Dephosphorylates RAF1 inhibiting its kinase activity. May act as a negative regulator of K-Ras signaling in membrane rafts. Involved in the hippocampus-dependent long-term memory formation. Involved in circadian control by regulating the consolidation of circadian periodicity after resetting. Involved in development and function of regulatory T-cells.
• 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 78% of tested tumors (at protein level). Ubiquitously expressed in non-cancerous tissues.
• 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

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Biomarker	[1]
Colonic neoplasm	DISSZ04P	Definitive	Biomarker	[1]
Colorectal neoplasm	DISR1UCN	Definitive	Altered Expression	[1]
Diabetic kidney disease	DISJMWEY	Definitive	Biomarker	[2]
Hyperglycemia	DIS0BZB5	Definitive	Altered Expression	[2]
Metastatic melanoma	DISSL43L	Definitive	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Astrocytoma	DISL3V18	Strong	Altered Expression	[7]
Cardiac arrest	DIS9DIA4	Strong	Altered Expression	[8]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[9]
Colon cancer	DISVC52G	Strong	Biomarker	[10]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[10]
Dementia	DISXL1WY	Strong	Biomarker	[11]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[12]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Gram-negative bacterial infection	DIS8MM3L	Strong	Altered Expression	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[14]
Huntington disease	DISQPLA4	Strong	Altered Expression	[15]
Hypopharyngeal squamous cell carcinoma	DISDDD65	Strong	Altered Expression	[16]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[17]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[18]
Lung cancer	DISCM4YA	Strong	Altered Expression	[19]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[19]
Lymphoma	DISN6V4S	Strong	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[20]
Obesity	DIS47Y1K	Strong	Biomarker	[21]
Osteoarthritis	DIS05URM	Strong	Biomarker	[22]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[6]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[5]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[23]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[24]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[16]
Coronary atherosclerosis	DISKNDYU	moderate	Altered Expression	[25]
Myocardial ischemia	DISFTVXF	moderate	Altered Expression	[25]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Biomarker	[9]
Prostate cancer	DISF190Y	moderate	Altered Expression	[23]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[5]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[26]
Gallbladder cancer	DISXJUAF	Limited	Altered Expression	[27]
Gallbladder carcinoma	DISD6ACL	Limited	Altered Expression	[27]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[28]
Melanoma	DIS1RRCY	Limited	Altered Expression	[3]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[28]
Tuberous sclerosis	DISEMUGZ	Limited	Biomarker	[29]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[30]

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 PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1).	[37]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1).	[33]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1).	[34]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1).	[35]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1).	[36]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1).	[38]

References

• [1] PHLPP is a negative regulator of RAF1, which reduces colorectal cancer cell motility and prevents tumor progression in mice.Gastroenterology. 2014 May;146(5):1301-12.e1-10. doi: 10.1053/j.gastro.2014.02.003. Epub 2014 Feb 11.
• [2] Activation of GSK3/-TrCP axis via PHLPP1 exacerbates Nrf2 degradation leading to impairment in cell survival pathway during diabetic nephropathy.Free Radic Biol Med. 2018 May 20;120:414-424. doi: 10.1016/j.freeradbiomed.2018.04.550. Epub 2018 Apr 12.
• [3] 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.
• [4] Role of PHLPP1 in inflammation response: Its loss contributes to gliomas development and progression.Int Immunopharmacol. 2016 May;34:229-234. doi: 10.1016/j.intimp.2016.02.034. Epub 2016 Mar 10.
• [5] Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells.Leukemia. 2010 Dec;24(12):2063-71. doi: 10.1038/leu.2010.201. Epub 2010 Sep 23.
• [6] Protein Kinase C Quality Control by Phosphatase PHLPP1Unveils Loss-of-Function Mechanism in Cancer.Mol Cell. 2019 Apr 18;74(2):378-392.e5. doi: 10.1016/j.molcel.2019.02.018. Epub 2019 Mar 20.
• [7] Mislocalization of the E3 ligase, -transducin repeat-containing protein 1 (-TrCP1), in glioblastoma uncouples negative feedback between the pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) and Akt.J Biol Chem. 2011 Jun 3;286(22):19777-88. doi: 10.1074/jbc.M111.237081. Epub 2011 Mar 28.
• [8] Pharmacological inhibition of pleckstrin homology domain leucine-rich repeat protein phosphatase is neuroprotective: differential effects on astrocytes.J Pharmacol Exp Ther. 2013 Nov;347(2):516-28. doi: 10.1124/jpet.113.206888. Epub 2013 Sep 10.
• [9] PHLPP: a putative cellular target during insulin resistance and type 2 diabetes.J Endocrinol. 2017 Jun;233(3):R185-R198. doi: 10.1530/JOE-17-0081. Epub 2017 Apr 20.
• [10] MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1.Expert Opin Ther Targets. 2015;19(8):1017-26. doi: 10.1517/14728222.2015.1057569. Epub 2015 Jun 24.
• [11] Selenium attenuates apoptosis, inflammation and oxidative stress in the blood and brain of aged rats with scopolamine-induced dementia.Metab Brain Dis. 2017 Apr;32(2):321-329. doi: 10.1007/s11011-016-9903-1. Epub 2016 Sep 15.
• [12] Expression and role of oncogenic miRNA-224 in esophageal squamous cell carcinoma.BMC Cancer. 2015 Aug 6;15:575. doi: 10.1186/s12885-015-1581-6.
• [13] Leptin signaling impairs macrophage defenses against Salmonella Typhimurium.Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16551-16560. doi: 10.1073/pnas.1904885116. Epub 2019 Jul 26.
• [14] miR-190 promotes HCC proliferation and metastasis by targeting PHLPP1.Exp Cell Res. 2018 Oct 1;371(1):185-195. doi: 10.1016/j.yexcr.2018.08.008. Epub 2018 Aug 6.
• [15] PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum.Cell Death Differ. 2010 Feb;17(2):324-35. doi: 10.1038/cdd.2009.127. Epub 2009 Sep 11.
• [16] 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.
• [17] Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice.Cell Death Dis. 2019 Oct 3;10(10):754. doi: 10.1038/s41419-019-1985-3.
• [18] 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.
• [19] USP1 regulates AKT phosphorylation by modulating the stability of PHLPP1 in lung cancer cells.J Cancer Res Clin Oncol. 2012 Jul;138(7):1231-8. doi: 10.1007/s00432-012-1193-3. Epub 2012 Mar 20.
• [20] MicroRNA-141 promotes the proliferation of non-small cell lung cancer cells by regulating expression of PHLPP1 and PHLPP2.FEBS Lett. 2014 Aug 25;588(17):3055-61. doi: 10.1016/j.febslet.2014.06.020. Epub 2014 Jun 16.
• [21] Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance.Diabetologia. 2011 Jul;54(7):1879-87. doi: 10.1007/s00125-011-2116-6. Epub 2011 Apr 1.
• [22] Phlpp inhibitors block pain and cartilage degradation associated with osteoarthritis.J Orthop Res. 2018 May;36(5):1487-1497. doi: 10.1002/jor.23781. Epub 2017 Nov 28.
• [23] Depletion of SAG/RBX2 E3 ubiquitin ligase suppresses prostate tumorigenesis via inactivation of the PI3K/AKT/mTOR axis.Mol Cancer. 2016 Dec 12;15(1):81. doi: 10.1186/s12943-016-0567-6.
• [24] Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP): a new player in cell signaling.J Biol Chem. 2012 Feb 3;287(6):3610-6. doi: 10.1074/jbc.R111.318675. Epub 2011 Dec 5.
• [25] Tumor necrosis factor-alpha upregulated PHLPP1 through activating nuclear factor-kappa B during myocardial ischemia/reperfusion.Life Sci. 2018 Aug 15;207:355-363. doi: 10.1016/j.lfs.2018.06.023. Epub 2018 Jun 22.
• [26] LncRNA PCAT1 activates AKT and NF-B signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKK complex.Nucleic Acids Res. 2019 May 7;47(8):4211-4225. doi: 10.1093/nar/gkz108.
• [27] SNORA74B gene silencing inhibits gallbladder cancer cells by inducing PHLPP and suppressing Akt/mTOR signaling.Oncotarget. 2017 Mar 21;8(12):19980-19996. doi: 10.18632/oncotarget.15301.
• [28] PHLPP negatively regulates cell motility through inhibition of Akt activity and integrin expression in pancreatic cancer cells.Oncotarget. 2016 Feb 16;7(7):7801-15. doi: 10.18632/oncotarget.6848.
• [29] The tuberous sclerosis complex subunit TBC1D7 is stabilized by Akt phosphorylation-mediated 14-3-3 binding.J Biol Chem. 2018 Oct 19;293(42):16142-16159. doi: 10.1074/jbc.RA118.003525. Epub 2018 Aug 24.
• [30] 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.
• [31] 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.
• [32] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [33] 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.
• [34] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [35] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [36] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [37] 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.
• [38] 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.
• [39] 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.