Molecule Information

General Information of the Molecule (ID: Mol00147)

• Name: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) ,Homo sapiens
• Synonyms: Protein-tyrosine phosphatase 1D; PTP-1D; Protein-tyrosine phosphatase 2C; PTP-2C; SH-PTP2; SHP-2; Shp2; SH-PTP3; PTP2C; SHPTP2
• Molecule Type: Protein
• Gene Name: PTPN11
• Gene ID: 5781
• Location: chr12:112418351-112509918[+]
• 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.
• Uniprot ID: PTN11_HUMAN
• Ensembl ID: ENSG00000179295
• HGNC ID: HGNC:9644

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hepatocellular carcinoma [1]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: 97H cells; Liver; Homo sapiens (Human); N.A.
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Flow cytometric analysis; Spheroid formation assay
• Mechanism Description: miR589-5p promotes the cancer stem cell characteristics and chemoresistance via targeting multiple negative regulators of STAT3 signaling pathway, including SOCS2, SOCS5, PTPN1 and PTPN11, leading to constitutive activation of STAT3 signaling.

Preclinical Drug(s) 3 drug(s) in total

Cryptotanshinone

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Juvenile myelomonocytic leukaemia [2]

• Sensitive Disease: Juvenile myelomonocytic leukaemia [ICD-11: 2A42.0]
• Sensitive Drug: Cryptotanshinone
• Molecule Alteration: Missense mutation; p.E76K (c.226G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of Cryptotanshinone by unusual activation of pro-survival pathway

II-B08

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hematologic Cancer [3]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: II-B08
• Molecule Alteration: Missense mutation; p.E76K (c.226G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: 3H-thymidine incorporation assay
• Mechanism Description: The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of II-B08 by unusual activation of pro-survival pathway

SHP099

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [4]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: SHP099
• Molecule Alteration: Missense mutation; p.E76K (c.226G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559

Disease Class: Acute myeloid leukemia [4]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: SHP099
• Molecule Alteration: Missense mutation; p.D61Y (c.181G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559

Disease Class: Acute myeloid leukemia [4]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Resistant Drug: SHP099
• Molecule Alteration: Missense mutation; p.A72V (c.215C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute myeloid leukemia [4]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Sensitive Drug: SHP099
• Molecule Alteration: Missense mutation; p.E69K (c.205G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559

Investigative Drug(s) 2 drug(s) in total

PD98059

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute lymphocytic leukemia [5]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Sensitive Drug: PD98059
• Molecule Alteration: Missense mutation; p.E76K (c.226G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of PD98059 by unusual activation of pro-survival pathway

U0126

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute lymphocytic leukemia [5]

• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Sensitive Drug: U0126
• Molecule Alteration: Missense mutation; p.E76K (c.226G>A)
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of U0126 by unusual activation of pro-survival pathway

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Acute myeloid leukemia [ICD-11: 2A60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Bone marrow
• The Specified Disease: Acute myeloid leukemia
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.25E-23; Fold-change: 2.78E-01; Z-score: 1.24E+00

Liver cancer [ICD-11: 2C12]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Liver
• The Specified Disease: Liver cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.46E-01; Fold-change: 9.97E-02; Z-score: 1.41E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 7.56E-18; Fold-change: 4.40E-01; Z-score: 8.85E-01
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 5.62E-01; Fold-change: 2.16E-01; Z-score: 2.50E-01

References

• Ref 1: Maintenance of stemness by miR-589-5p in hepatocellular carcinoma cells promotes chemoresistance via STAT3 signaling. Cancer Lett. 2018 Jun 1;423:113-126. doi: 10.1016/j.canlet.2017.11.031. Epub 2017 Nov 28.
• Ref 2: Identification of cryptotanshinone as an inhibitor of oncogenic protein tyrosine phosphatase SHP2 (PTPN11)J Med Chem. 2013 Sep 26;56(18):7212-21. doi: 10.1021/jm400474r. Epub 2013 Sep 4.
• Ref 3: Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)J Med Chem. 2010 Mar 25;53(6):2482-93. doi: 10.1021/jm901645u.
• Ref 4: Selective inhibition of leukemia-associated SHP2(E69K) mutant by the allosteric SHP2 inhibitor SHP099Leukemia. 2018 May;32(5):1246-1249. doi: 10.1038/s41375-018-0020-5. Epub 2018 Jan 30.
• Ref 5: Shp2E76K mutant confers cytokine-independent survival of TF-1 myeloid cells by up-regulating Bcl-XLJ Biol Chem. 2007 Dec 14;282(50):36463-73. doi: 10.1074/jbc.M705789200. Epub 2007 Oct 17.