Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFH9M73)

• DOT Name: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11)
• Synonyms: EC 3.1.3.48; Protein-tyrosine phosphatase 1D; PTP-1D; Protein-tyrosine phosphatase 2C; PTP-2C; SH-PTP2; SHP-2; Shp2; SH-PTP3
• Gene Name: PTPN11
• Related Disease:
  LEOPARD syndrome 1
  Noonan syndrome
  Noonan syndrome 1
  Noonan syndrome and Noonan-related syndrome
  Noonan syndrome with multiple lentigines
  Metachondromatosis
  Cardiofaciocutaneous syndrome
  Costello syndrome
• UniProt ID: PTN11_HUMAN
• PDB ID: 2SHP ; 3B7O ; 3MOW ; 3O5X ; 3TKZ ; 3TL0 ; 3ZM0 ; 3ZM1 ; 3ZM2 ; 3ZM3 ; 4DGP ; 4DGX ; 4GWF ; 4H1O ; 4H34 ; 4JE4 ; 4JEG ; 4JMG ; 4NWF ; 4NWG ; 4OHD ; 4OHE ; 4OHH ; 4OHI ; 4OHL ; 4PVG ; 4QSY ; 4RDD ; 5BK8 ; 5DF6 ; 5EHP ; 5EHR ; 5I6V ; 5IBM ; 5IBS ; 5X7B ; 5X94 ; 5XZR ; 6ATD ; 6BMR ; 6BMU ; 6BMV ; 6BMW ; 6BMX ; 6BMY ; 6BN5 ; 6CMP ; 6CMQ ; 6CMR ; 6CMS ; 6CRF ; 6CRG ; 6MD7 ; 6MD9 ; 6MDA ; 6MDB ; 6MDC ; 6MDD ; 6R5G ; 6WU8 ; 7EMN ; 7JVM ; 7JVN ; 7R75 ; 7R7D ; 7R7I ; 7R7L ; 7RCT ; 7TVJ ; 7VXG ; 7XHQ ; 8B5Y ; 8CBH ; 8GWW ; 8T6D ; 8T6G ; 8T7Q ; 8T8Q ; 8WFY
• EC Number: 3.1.3.48
• Pfam ID: PF00017 ; PF00102
• Sequence:
  MTSRRWFHPNITGVEAENLLLTRGVDGSFLARPSKSNPGDFTLSVRRNGAVTHIKIQNTG
  DYYDLYGGEKFATLAELVQYYMEHHGQLKEKNGDVIELKYPLNCADPTSERWFHGHLSGK
  EAEKLLTEKGKHGSFLVRESQSHPGDFVLSVRTGDDKGESNDGKSKVTHVMIRCQELKYD
  VGGGERFDSLTDLVEHYKKNPMVETLGTVLQLKQPLNTTRINAAEIESRVRELSKLAETT
  DKVKQGFWEEFETLQQQECKLLYSRKEGQRQENKNKNRYKNILPFDHTRVVLHDGDPNEP
  VSDYINANIIMPEFETKCNNSKPKKSYIATQGCLQNTVNDFWRMVFQENSRVIVMTTKEV
  ERGKSKCVKYWPDEYALKEYGVMRVRNVKESAAHDYTLRELKLSKVGQGNTERTVWQYHF
  RTWPDHGVPSDPGGVLDFLEEVHHKQESIMDAGPVVVHCSAGIGRTGTFIVIDILIDIIR
  EKGVDCDIDVPKTIQMVRSQRSGMVQTEAQYRFIYMAVQHYIETLQRRIEEEQKSKRKGH
  EYTNIKYSLADQTSGDQSPLPPCTPTPPCAEMREDSARVYENVGLMQQQKSFR
• Function: Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. Positively regulates MAPK signal transduction pathway. Dephosphorylates GAB1, ARHGAP35 and EGFR. Dephosphorylates ROCK2 at 'Tyr-722' resulting in stimulation of its RhoA binding activity. Dephosphorylates CDC73. Dephosphorylates SOX9 on tyrosine residues, leading to inactivate SOX9 and promote ossification. Dephosphorylates tyrosine-phosphorylated NEDD9/CAS-L.
• Tissue Specificity: Widely expressed, with highest levels in heart, brain, and skeletal muscle.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Phospholipase D sig.ling pathway (hsa04072)
  Efferocytosis (hsa04148)
  Axon guidance (hsa04360)
  C-type lectin receptor sig.ling pathway (hsa04625)
  JAK-STAT sig.ling pathway (hsa04630)
  .tural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor sig.ling pathway (hsa04660)
  Leukocyte transendothelial migration (hsa04670)
  Neurotrophin sig.ling pathway (hsa04722)
  Adipocytokine sig.ling pathway (hsa04920)
  Insulin resistance (hsa04931)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Pathogenic Escherichia coli infection (hsa05130)
  Herpes simplex virus 1 infection (hsa05168)
  Proteoglycans in cancer (hsa05205)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Re.l cell carcinoma (hsa05211)
  Chronic myeloid leukemia (hsa05220)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway:
  PI3K Cascade (R-HSA-109704)
  MAPK3 (ERK1) activation (R-HSA-110056)
  MAPK1 (ERK2) activation (R-HSA-112411)
  GPVI-mediated activation cascade (R-HSA-114604)
  Prolactin receptor signaling (R-HSA-1170546)
  PIP3 activates AKT signaling (R-HSA-1257604)
  Spry regulation of FGF signaling (R-HSA-1295596)
  Signaling by SCF-KIT (R-HSA-1433557)
  GAB1 signalosome (R-HSA-180292)
  Downstream signal transduction (R-HSA-186763)
  PECAM1 interactions (R-HSA-210990)
  Tie2 Signaling (R-HSA-210993)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  Signaling by Leptin (R-HSA-2586552)
  Costimulation by the CD28 family (R-HSA-388841)
  CTLA4 inhibitory signaling (R-HSA-389513)
  PD-1 signaling (R-HSA-389948)
  Signal regulatory protein family interactions (R-HSA-391160)
  Netrin mediated repulsion signals (R-HSA-418886)
  Platelet sensitization by LDL (R-HSA-432142)
  Interleukin-3, Interleukin-5 and GM-CSF signaling (R-HSA-512988)
  PI-3K cascade (R-HSA-5654689)
  FRS-mediated FGFR1 signaling (R-HSA-5654693)
  PI-3K cascade (R-HSA-5654695)
  FRS-mediated FGFR2 signaling (R-HSA-5654700)
  FRS-mediated FGFR3 signaling (R-HSA-5654706)
  PI-3K cascade (R-HSA-5654710)
  FRS-mediated FGFR4 signaling (R-HSA-5654712)
  PI-3K cascade (R-HSA-5654720)
  Negative regulation of FGFR1 signaling (R-HSA-5654726)
  Negative regulation of FGFR2 signaling (R-HSA-5654727)
  Negative regulation of FGFR3 signaling (R-HSA-5654732)
  Negative regulation of FGFR4 signaling (R-HSA-5654733)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Regulation of IFNG signaling (R-HSA-877312)
  RET signaling (R-HSA-8853659)
  Interleukin-20 family signaling (R-HSA-8854691)
  MET activates PTPN11 (R-HSA-8865999)
  Regulation of RUNX1 Expression and Activity (R-HSA-8934593)
  Interleukin-37 signaling (R-HSA-9008059)
  Activated NTRK2 signals through FRS2 and FRS3 (R-HSA-9028731)
  Interferon alpha/beta signaling (R-HSA-909733)
  Regulation of IFNA/IFNB signaling (R-HSA-912694)
  Activation of IRF3, IRF7 mediated by TBK1, IKK (IKBKE) (R-HSA-936964)
  FLT3 Signaling (R-HSA-9607240)
  STAT5 Activation (R-HSA-9645135)
  Signaling by CSF3 (G-CSF) (R-HSA-9674555)
  Signaling by CSF1 (M-CSF) in myeloid cells (R-HSA-9680350)
  STAT5 activation downstream of FLT3 ITD mutants (R-HSA-9702518)
  Signaling by FLT3 ITD and TKD mutants (R-HSA-9703648)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Interleukin-6 signaling (R-HSA-1059683)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
LEOPARD syndrome 1	DIS3WUB8	Definitive	Autosomal dominant	[1]
Noonan syndrome	DIS7Q7DN	Definitive	Autosomal dominant	[2]
Noonan syndrome 1	DIS7M92N	Definitive	Autosomal dominant	[3]
Noonan syndrome and Noonan-related syndrome	DISTATYK	Definitive	Autosomal dominant	[4]
Noonan syndrome with multiple lentigines	DIS014D0	Definitive	Autosomal dominant	[2]
Metachondromatosis	DISUM6CO	Strong	Autosomal dominant	[5]
Cardiofaciocutaneous syndrome	DISZJKSC	Disputed	Autosomal dominant	[2]
Costello syndrome	DISXVJH3	Disputed	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chondroitin sulfate	DM0N19Y	Phase 4	Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) affects the binding of Chondroitin sulfate.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[13]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[14]
Gemcitabine	DMSE3I7	Approved	Gemcitabine affects the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[16]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the activity of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[18]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[21]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[18]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[22]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[18]
Methyl Mercury Ion	DM6YEW4	Investigative	Methyl Mercury Ion increases the expression of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[18]
Pervanadate	DM873BS	Investigative	Pervanadate decreases the activity of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[23]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tyrosine-protein phosphatase non-receptor type 11 (PTPN11).	[19]

References

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• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019 Nov;51(11):1560-1565. doi: 10.1038/s41588-019-0528-2.
• [4] PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006 Mar 10;281(10):6785-92. doi: 10.1074/jbc.M513068200. Epub 2005 Dec 23.
• [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] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] ATPR induces acute promyelocytic leukemia cells differentiation and growth arrest by blockade of SHP2/Rho/ROCK1 pathway. Toxicol Appl Pharmacol. 2020 Jul 15;399:115053. doi: 10.1016/j.taap.2020.115053. Epub 2020 May 15.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] Arsenic trioxide induces apoptosis in NB-4, an acute promyelocytic leukemia cell line, through up-regulation of p73 via suppression of nuclear factor kappa B-mediated inhibition of p73 transcription and prevention of NF-kappaB-mediated induction of XIAP, cIAP2, BCL-XL and survivin. Med Oncol. 2010 Sep;27(3):833-42. doi: 10.1007/s12032-009-9294-9. Epub 2009 Sep 10.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [15] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [16] Resveratrol attenuates constitutive STAT3 and STAT5 activation through induction of PTP and SHP-2 tyrosine phosphatases and potentiates sorafenib-induced apoptosis in renal cell carcinoma. BMC Nephrol. 2016 Feb 25;17:19. doi: 10.1186/s12882-016-0233-7.
• [17] Regulation of growth hormone signaling by selective estrogen receptor modulators occurs through suppression of protein tyrosine phosphatases. Endocrinology. 2007 May;148(5):2417-23. doi: 10.1210/en.2006-1305. Epub 2007 Feb 1.
• [18] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.
• [19] 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.
• [20] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [23] Osteosarcoma cell proliferation suppression via SHP-2-mediated inactivation of the JAK/STAT3 pathway by tubocapsenolide A. J Adv Res. 2021 Jun 11;34:79-91. doi: 10.1016/j.jare.2021.06.004. eCollection 2021 Dec.
• [24] Decline in arylsulfatase B expression increases EGFR expression by inhibiting the protein-tyrosine phosphatase SHP2 and activating JNK in prostate cells. J Biol Chem. 2018 Jul 13;293(28):11076-11087. doi: 10.1074/jbc.RA117.001244. Epub 2018 May 24.