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
    Click to Show/Hide
Molecule Type
Protein
Gene Name
PTPN11
Gene ID
5781
Location
chr12:112418351-112509918[+]
Sequence
MTSRRWFHPNITGVEAENLLLTRGVDGSFLARPSKSNPGDFTLSVRRNGAVTHIKIQNTG
DYYDLYGGEKFATLAELVQYYMEHHGQLKEKNGDVIELKYPLNCADPTSERWFHGHLSGK
EAEKLLTEKGKHGSFLVRESQSHPGDFVLSVRTGDDKGESNDGKSKVTHVMIRCQELKYD
VGGGERFDSLTDLVEHYKKNPMVETLGTVLQLKQPLNTTRINAAEIESRVRELSKLAETT
DKVKQGFWEEFETLQQQECKLLYSRKEGQRQENKNKNRYKNILPFDHTRVVLHDGDPNEP
VSDYINANIIMPEFETKCNNSKPKKSYIATQGCLQNTVNDFWRMVFQENSRVIVMTTKEV
ERGKSKCVKYWPDEYALKEYGVMRVRNVKESAAHDYTLRELKLSKVGQGNTERTVWQYHF
RTWPDHGVPSDPGGVLDFLEEVHHKQESIMDAGPVVVHCSAGIGRTGTFIVIDILIDIIR
EKGVDCDIDVPKTIQMVRSQRSGMVQTEAQYRFIYMAVQHYIETLQRRIEEEQKSKRKGH
EYTNIKYSLADQTSGDQSPLPPCTPTPPCAEMREDSARVYENVGLMQQQKSFR
    Click to Show/Hide
3D-structure
PDB ID
8U7W
Classification
Hydrolase/inhibitor
Method
X-ray diffraction
Resolution
2.05  Å
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.
    Click to Show/Hide
Uniprot ID
PTN11_HUMAN
Ensembl ID
ENSG00000179295
HGNC ID
HGNC:9644
        Click to Show/Hide the Complete Species Lineage
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
Click to Show/Hide the Full List of Drugs
Doxorubicin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.2] [1]
Resistant Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
Differential expression of the molecule in resistant disease
Classification of Disease Liver cancer [ICD-11: 2C12]
The Specified Disease Hepatocellular carcinoma
The Studied Tissue Liver tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 6.92E-03
Fold-change: -6.39E-02
Z-score: -2.73E+00
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
HepG2 cells Liver Homo sapiens (Human) CVCL_0027
Hep3B cells Liver Homo sapiens (Human) CVCL_0326
QGY-7703 cells Liver Homo sapiens (Human) CVCL_6715
SMMC7721 cells Uterus Homo sapiens (Human) CVCL_0534
97H cells Liver Homo sapiens (Human) N.A.
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
Click to Show/Hide the Full List of Drugs
Cryptotanshinone
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Juvenile myelomonocytic leukaemia [ICD-11: 2A42.0] [2]
Sensitive Disease Juvenile myelomonocytic leukaemia [ICD-11: 2A42.0]
 Disease Info 
Sensitive Drug Cryptotanshinone
 Drug Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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100
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160
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170
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180
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190
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280
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340
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L
Click to Show/Hide the Structure
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 blot 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
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Hematologic Cancer [ICD-11: MG24.Y] [3]
Sensitive Disease Hematologic Cancer [ICD-11: MG24.Y]
 Disease Info 
Sensitive Drug II-B08
 Drug Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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0
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M
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E
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120
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E
160
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N
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D
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G
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H
170
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V
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210
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220
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N
A
A
A
A
E
E
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R
230
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V
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240
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T
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250
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E
E
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C
260
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K
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L
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Y
Y
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R
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E
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G
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Q
270
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R
R
Q
Q
E
E
N
N
K
K
N
N
K
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N
N
R
R
Y
Y
280
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K
K
N
N
I
I
L
L
P
P
F
F
D
D
H
H
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T
R
R
290
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V
V
V
V
L
L
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H
D
D
G
G
D
D
P
P
N
N
E
E
300
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P
P
V
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S
S
D
D
Y
Y
I
I
N
N
A
A
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I
I
310
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I
I
M
M
P
P
E
E
F
F
E
E
T
T
K
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C
C
N
N
320
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N
N
S
S
K
K
P
P
K
K
K
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S
Y
Y
I
I
A
A
330
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T
T
Q
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G
G
C
C
L
L
Q
Q
N
N
T
T
V
V
N
N
340
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D
D
F
F
W
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M
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F
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E
N
N
350
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T
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E
E
360
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V
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E
E
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R
G
G
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K
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S
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K
C
C
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K
370
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Y
Y
W
W
P
P
D
D
E
E
Y
Y
A
A
L
L
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K
E
E
380
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Y
Y
G
G
V
V
M
M
R
R
V
V
R
R
N
N
V
V
K
K
390
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E
E
S
S
A
A
A
A
H
H
D
D
Y
Y
T
T
L
L
R
R
400
|
E
E
L
L
K
K
L
L
S
S
K
K
V
V
G
G
Q
Q
G
G
410
|
N
N
T
T
E
E
R
R
T
T
V
V
W
W
Q
Q
Y
Y
H
H
420
|
F
F
R
R
T
T
W
W
P
P
D
D
H
H
G
G
V
V
P
P
430
|
S
S
D
D
P
P
G
G
G
G
V
V
L
L
D
D
F
F
L
L
440
|
E
E
E
E
V
V
H
H
H
H
K
K
Q
Q
E
E
S
S
I
I
450
|
M
M
D
D
A
A
G
G
P
P
V
V
V
V
V
V
H
H
C
C
460
|
S
S
A
A
G
G
I
I
G
G
R
R
T
T
G
G
T
T
F
F
470
|
I
I
V
V
I
I
D
D
I
I
L
L
I
I
D
D
I
I
I
I
480
|
R
R
E
E
K
K
G
G
V
V
D
D
C
C
D
D
I
I
D
D
490
|
V
V
P
P
K
K
T
T
I
I
Q
Q
M
M
V
V
R
R
S
S
500
|
Q
Q
R
R
S
S
G
G
M
M
V
V
Q
Q
T
T
E
E
A
A
510
|
Q
Q
Y
Y
R
R
F
F
I
I
Y
Y
M
M
A
A
V
V
Q
Q
520
|
H
H
Y
Y
I
I
E
E
T
T
L
L
Click to Show/Hide the Structure
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 blot 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
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [4]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Resistant Drug SHP099
 Drug Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
S
G
M
M
T
T
S
S
R
R
R
R
W
W
F
F
H
H
P
P
10
|
N
N
I
I
T
T
G
G
V
V
E
E
A
A
E
E
N
N
L
L
20
|
L
L
L
L
T
T
R
R
G
G
V
V
D
D
G
G
S
S
F
F
30
|
L
L
A
A
R
R
P
P
S
S
K
K
S
S
N
N
P
P
G
G
40
|
D
D
F
F
T
T
L
L
S
S
V
V
R
R
R
R
N
N
G
G
50
|
A
A
V
V
T
T
H
H
I
I
K
K
I
I
Q
Q
N
N
T
T
60
|
G
G
D
D
Y
Y
Y
Y
D
D
L
L
Y
Y
G
G
G
G
E
E
70
|
K
K
F
F
A
A
T
T
L
L
A
A
E
K
L
L
V
V
Q
Q
80
|
Y
Y
Y
Y
M
M
E
E
H
H
H
H
G
G
Q
Q
L
L
K
K
90
|
E
E
K
K
N
N
G
G
D
D
V
V
I
I
E
E
L
L
K
K
100
|
Y
Y
P
P
L
L
N
N
C
C
A
A
D
D
P
P
T
T
S
S
110
|
E
E
R
R
W
W
F
F
H
H
G
G
H
H
L
L
S
S
G
G
120
|
K
K
E
E
A
A
E
E
K
K
L
L
L
L
T
T
E
E
K
K
130
|
G
G
K
K
H
H
G
G
S
S
F
F
L
L
V
V
R
R
E
E
140
|
S
S
Q
Q
S
S
H
H
P
P
G
G
D
D
F
F
V
V
L
L
150
|
S
S
V
V
R
R
T
T
G
G
D
D
D
D
K
K
G
G
E
E
160
|
S
S
N
N
D
D
G
G
K
K
S
S
K
K
V
V
T
T
H
H
170
|
V
V
M
M
I
I
R
R
C
C
Q
Q
E
E
L
L
K
K
Y
Y
180
|
D
D
V
V
G
G
G
G
G
G
E
E
R
R
F
F
D
D
S
S
190
|
L
L
T
T
D
D
L
L
V
V
E
E
H
H
Y
Y
K
K
K
K
200
|
N
N
P
P
M
M
V
V
E
E
T
T
L
L
G
G
T
T
V
V
210
|
L
L
Q
Q
L
L
K
K
Q
Q
P
P
L
L
N
N
T
T
T
T
220
|
R
R
I
I
N
N
A
A
A
A
E
E
I
I
E
E
S
S
R
R
230
|
V
V
R
R
E
E
L
L
S
S
K
K
L
L
A
A
E
E
T
T
240
|
T
T
D
D
K
K
V
V
K
K
Q
Q
G
G
F
F
W
W
E
E
250
|
E
E
F
F
E
E
T
T
L
L
Q
Q
Q
Q
Q
Q
E
E
C
C
260
|
K
K
L
L
L
L
Y
Y
S
S
R
R
K
K
E
E
G
G
Q
Q
270
|
R
R
Q
Q
E
E
N
N
K
K
N
N
K
K
N
N
R
R
Y
Y
280
|
K
K
N
N
I
I
L
L
P
P
F
F
D
D
H
H
T
T
R
R
290
|
V
V
V
V
L
L
H
H
D
D
G
G
D
D
P
P
N
N
E
E
300
|
P
P
V
V
S
S
D
D
Y
Y
I
I
N
N
A
A
N
N
I
I
310
|
I
I
M
M
P
P
E
E
F
F
E
E
T
T
K
K
C
C
N
N
320
|
N
N
S
S
K
K
P
P
K
K
K
K
S
S
Y
Y
I
I
A
A
330
|
T
T
Q
Q
G
G
C
C
L
L
Q
Q
N
N
T
T
V
V
N
N
340
|
D
D
F
F
W
W
R
R
M
M
V
V
F
F
Q
Q
E
E
N
N
350
|
S
S
R
R
V
V
I
I
V
V
M
M
T
T
T
T
K
K
E
E
360
|
V
V
E
E
R
R
G
G
K
K
S
S
K
K
C
C
V
V
K
K
370
|
Y
Y
W
W
P
P
D
D
E
E
Y
Y
A
A
L
L
K
K
E
E
380
|
Y
Y
G
G
V
V
M
M
R
R
V
V
R
R
N
N
V
V
K
K
390
|
E
E
S
S
A
A
A
A
H
H
D
D
Y
Y
T
T
L
L
R
R
400
|
E
E
L
L
K
K
L
L
S
S
K
K
V
V
G
G
Q
Q
G
G
410
|
N
N
T
T
E
E
R
R
T
T
V
V
W
W
Q
Q
Y
Y
H
H
420
|
F
F
R
R
T
T
W
W
P
P
D
D
H
H
G
G
V
V
P
P
430
|
S
S
D
D
P
P
G
G
G
G
V
V
L
L
D
D
F
F
L
L
440
|
E
E
E
E
V
V
H
H
H
H
K
K
Q
Q
E
E
S
S
I
I
450
|
M
M
D
D
A
A
G
G
P
P
V
V
V
V
V
V
H
H
C
C
460
|
S
S
A
A
G
G
I
I
G
G
R
R
T
T
G
G
T
T
F
F
470
|
I
I
V
V
I
I
D
D
I
I
L
L
I
I
D
D
I
I
I
I
480
|
R
R
E
E
K
K
G
G
V
V
D
D
C
C
D
D
I
I
D
D
490
|
V
V
P
P
K
K
T
T
I
I
Q
Q
M
M
V
V
R
R
S
S
500
|
Q
Q
R
R
S
S
G
G
M
M
V
V
Q
Q
T
T
E
E
A
A
510
|
Q
Q
Y
Y
R
R
F
F
I
I
Y
Y
M
M
A
A
V
V
Q
Q
520
|
H
H
Y
Y
I
I
E
E
T
T
L
L
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model TF-1 cells Bone marrow Homo sapiens (Human) CVCL_0559
Mechanism Description The SHP2 variant carrying the potent activating mutation E76K exhibits an open-state structure, which induces drastic domain reorganization to expose the active site and eliminate the binding pocket for the allosteric inhibitor SHP099.
Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [4]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Resistant Drug SHP099
 Drug Info 
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 [ICD-11: 2A60.0] [4]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Resistant Drug SHP099
 Drug Info 
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) Click to Show/Hide
Disease Class: Acute myeloid leukemia [ICD-11: 2A60.0] [4]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Sensitive Drug SHP099
 Drug Info 
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
Disease Class: Thyroid gland cancer [ICD-11: 2D10.0] [5]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
 Disease Info 
Sensitive Drug SHP099
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MAPK/ERK signaling pathway Inhibition hsa04011
In Vitro Model K1 cells Thyroid Homo sapiens (Human) CVCL_2537
BCPAP cells Thyroid Homo sapiens (Human) CVCL_0153
KTC-1 cells Thyroid Homo sapiens (Human) CVCL_6300
8305C cells Thyroid Homo sapiens (Human) CVCL_1053
BHT-101 cells Thyroid gland Homo sapiens (Human) CVCL_1085
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot assay; RT-qPCR
Experiment for
Drug Resistance		 Cell proliferation capacity assay
Mechanism Description In treating thyroid cancer cells with vemurafenib, we have detected reactivation of the MAPK/ERK signaling pathway as a result of the release of multiple receptor tyrosine kinases (RTKs) from the negative feedback of ERK phosphorylation. SHP2 is an important target protein downstream of the RTK signaling pathway. Decreasing it through SHP2 knockdown or the use of an inhibitor of SHP2 (SHP099) was found to significantly increase the early sensitivity and reverse the late resistance to vemurafenib in BRAFV600E mutant thyroid cancer cells.Blocking SHP2 reverses the reactivation of the MAPK/ERK signaling pathway caused by the activation of RTKs and improves the sensitivity of thyroid cancer to vemurafenib.
Investigative Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
PD98059
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Acute lymphocytic leukemia [ICD-11: 2B33.0] [6]
Sensitive Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Sensitive Drug PD98059
 Drug Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
S
G
M
M
T
T
S
S
R
R
R
R
W
W
F
F
H
H
P
P
10
|
N
N
I
I
T
T
G
G
V
V
E
E
A
A
E
E
N
N
L
L
20
|
L
L
L
L
T
T
R
R
G
G
V
V
D
D
G
G
S
S
F
F
30
|
L
L
A
A
R
R
P
P
S
S
K
K
S
S
N
N
P
P
G
G
40
|
D
D
F
F
T
T
L
L
S
S
V
V
R
R
R
R
N
N
G
G
50
|
A
A
V
V
T
T
H
H
I
I
K
K
I
I
Q
Q
N
N
T
T
60
|
G
G
D
D
Y
Y
Y
Y
D
D
L
L
Y
Y
G
G
G
G
E
E
70
|
K
K
F
F
A
A
T
T
L
L
A
A
E
K
L
L
V
V
Q
Q
80
|
Y
Y
Y
Y
M
M
E
E
H
H
H
H
G
G
Q
Q
L
L
K
K
90
|
E
E
K
K
N
N
G
G
D
D
V
V
I
I
E
E
L
L
K
K
100
|
Y
Y
P
P
L
L
N
N
C
C
A
A
D
D
P
P
T
T
S
S
110
|
E
E
R
R
W
W
F
F
H
H
G
G
H
H
L
L
S
S
G
G
120
|
K
K
E
E
A
A
E
E
K
K
L
L
L
L
T
T
E
E
K
K
130
|
G
G
K
K
H
H
G
G
S
S
F
F
L
L
V
V
R
R
E
E
140
|
S
S
Q
Q
S
S
H
H
P
P
G
G
D
D
F
F
V
V
L
L
150
|
S
S
V
V
R
R
T
T
G
G
D
D
D
D
K
K
G
G
E
E
160
|
S
S
N
N
D
D
G
G
K
K
S
S
K
K
V
V
T
T
H
H
170
|
V
V
M
M
I
I
R
R
C
C
Q
Q
E
E
L
L
K
K
Y
Y
180
|
D
D
V
V
G
G
G
G
G
G
E
E
R
R
F
F
D
D
S
S
190
|
L
L
T
T
D
D
L
L
V
V
E
E
H
H
Y
Y
K
K
K
K
200
|
N
N
P
P
M
M
V
V
E
E
T
T
L
L
G
G
T
T
V
V
210
|
L
L
Q
Q
L
L
K
K
Q
Q
P
P
L
L
N
N
T
T
T
T
220
|
R
R
I
I
N
N
A
A
A
A
E
E
I
I
E
E
S
S
R
R
230
|
V
V
R
R
E
E
L
L
S
S
K
K
L
L
A
A
E
E
T
T
240
|
T
T
D
D
K
K
V
V
K
K
Q
Q
G
G
F
F
W
W
E
E
250
|
E
E
F
F
E
E
T
T
L
L
Q
Q
Q
Q
Q
Q
E
E
C
C
260
|
K
K
L
L
L
L
Y
Y
S
S
R
R
K
K
E
E
G
G
Q
Q
270
|
R
R
Q
Q
E
E
N
N
K
K
N
N
K
K
N
N
R
R
Y
Y
280
|
K
K
N
N
I
I
L
L
P
P
F
F
D
D
H
H
T
T
R
R
290
|
V
V
V
V
L
L
H
H
D
D
G
G
D
D
P
P
N
N
E
E
300
|
P
P
V
V
S
S
D
D
Y
Y
I
I
N
N
A
A
N
N
I
I
310
|
I
I
M
M
P
P
E
E
F
F
E
E
T
T
K
K
C
C
N
N
320
|
N
N
S
S
K
K
P
P
K
K
K
K
S
S
Y
Y
I
I
A
A
330
|
T
T
Q
Q
G
G
C
C
L
L
Q
Q
N
N
T
T
V
V
N
N
340
|
D
D
F
F
W
W
R
R
M
M
V
V
F
F
Q
Q
E
E
N
N
350
|
S
S
R
R
V
V
I
I
V
V
M
M
T
T
T
T
K
K
E
E
360
|
V
V
E
E
R
R
G
G
K
K
S
S
K
K
C
C
V
V
K
K
370
|
Y
Y
W
W
P
P
D
D
E
E
Y
Y
A
A
L
L
K
K
E
E
380
|
Y
Y
G
G
V
V
M
M
R
R
V
V
R
R
N
N
V
V
K
K
390
|
E
E
S
S
A
A
A
A
H
H
D
D
Y
Y
T
T
L
L
R
R
400
|
E
E
L
L
K
K
L
L
S
S
K
K
V
V
G
G
Q
Q
G
G
410
|
N
N
T
T
E
E
R
R
T
T
V
V
W
W
Q
Q
Y
Y
H
H
420
|
F
F
R
R
T
T
W
W
P
P
D
D
H
H
G
G
V
V
P
P
430
|
S
S
D
D
P
P
G
G
G
G
V
V
L
L
D
D
F
F
L
L
440
|
E
E
E
E
V
V
H
H
H
H
K
K
Q
Q
E
E
S
S
I
I
450
|
M
M
D
D
A
A
G
G
P
P
V
V
V
V
V
V
H
H
C
C
460
|
S
S
A
A
G
G
I
I
G
G
R
R
T
T
G
G
T
T
F
F
470
|
I
I
V
V
I
I
D
D
I
I
L
L
I
I
D
D
I
I
I
I
480
|
R
R
E
E
K
K
G
G
V
V
D
D
C
C
D
D
I
I
D
D
490
|
V
V
P
P
K
K
T
T
I
I
Q
Q
M
M
V
V
R
R
S
S
500
|
Q
Q
R
R
S
S
G
G
M
M
V
V
Q
Q
T
T
E
E
A
A
510
|
Q
Q
Y
Y
R
R
F
F
I
I
Y
Y
M
M
A
A
V
V
Q
Q
520
|
H
H
Y
Y
I
I
E
E
T
T
L
L
Click to Show/Hide the Structure
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
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Acute lymphocytic leukemia [ICD-11: 2B33.0] [6]
Sensitive Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
 Disease Info 
Sensitive Drug U0126
 Drug Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
S
G
M
M
T
T
S
S
R
R
R
R
W
W
F
F
H
H
P
P
10
|
N
N
I
I
T
T
G
G
V
V
E
E
A
A
E
E
N
N
L
L
20
|
L
L
L
L
T
T
R
R
G
G
V
V
D
D
G
G
S
S
F
F
30
|
L
L
A
A
R
R
P
P
S
S
K
K
S
S
N
N
P
P
G
G
40
|
D
D
F
F
T
T
L
L
S
S
V
V
R
R
R
R
N
N
G
G
50
|
A
A
V
V
T
T
H
H
I
I
K
K
I
I
Q
Q
N
N
T
T
60
|
G
G
D
D
Y
Y
Y
Y
D
D
L
L
Y
Y
G
G
G
G
E
E
70
|
K
K
F
F
A
A
T
T
L
L
A
A
E
K
L
L
V
V
Q
Q
80
|
Y
Y
Y
Y
M
M
E
E
H
H
H
H
G
G
Q
Q
L
L
K
K
90
|
E
E
K
K
N
N
G
G
D
D
V
V
I
I
E
E
L
L
K
K
100
|
Y
Y
P
P
L
L
N
N
C
C
A
A
D
D
P
P
T
T
S
S
110
|
E
E
R
R
W
W
F
F
H
H
G
G
H
H
L
L
S
S
G
G
120
|
K
K
E
E
A
A
E
E
K
K
L
L
L
L
T
T
E
E
K
K
130
|
G
G
K
K
H
H
G
G
S
S
F
F
L
L
V
V
R
R
E
E
140
|
S
S
Q
Q
S
S
H
H
P
P
G
G
D
D
F
F
V
V
L
L
150
|
S
S
V
V
R
R
T
T
G
G
D
D
D
D
K
K
G
G
E
E
160
|
S
S
N
N
D
D
G
G
K
K
S
S
K
K
V
V
T
T
H
H
170
|
V
V
M
M
I
I
R
R
C
C
Q
Q
E
E
L
L
K
K
Y
Y
180
|
D
D
V
V
G
G
G
G
G
G
E
E
R
R
F
F
D
D
S
S
190
|
L
L
T
T
D
D
L
L
V
V
E
E
H
H
Y
Y
K
K
K
K
200
|
N
N
P
P
M
M
V
V
E
E
T
T
L
L
G
G
T
T
V
V
210
|
L
L
Q
Q
L
L
K
K
Q
Q
P
P
L
L
N
N
T
T
T
T
220
|
R
R
I
I
N
N
A
A
A
A
E
E
I
I
E
E
S
S
R
R
230
|
V
V
R
R
E
E
L
L
S
S
K
K
L
L
A
A
E
E
T
T
240
|
T
T
D
D
K
K
V
V
K
K
Q
Q
G
G
F
F
W
W
E
E
250
|
E
E
F
F
E
E
T
T
L
L
Q
Q
Q
Q
Q
Q
E
E
C
C
260
|
K
K
L
L
L
L
Y
Y
S
S
R
R
K
K
E
E
G
G
Q
Q
270
|
R
R
Q
Q
E
E
N
N
K
K
N
N
K
K
N
N
R
R
Y
Y
280
|
K
K
N
N
I
I
L
L
P
P
F
F
D
D
H
H
T
T
R
R
290
|
V
V
V
V
L
L
H
H
D
D
G
G
D
D
P
P
N
N
E
E
300
|
P
P
V
V
S
S
D
D
Y
Y
I
I
N
N
A
A
N
N
I
I
310
|
I
I
M
M
P
P
E
E
F
F
E
E
T
T
K
K
C
C
N
N
320
|
N
N
S
S
K
K
P
P
K
K
K
K
S
S
Y
Y
I
I
A
A
330
|
T
T
Q
Q
G
G
C
C
L
L
Q
Q
N
N
T
T
V
V
N
N
340
|
D
D
F
F
W
W
R
R
M
M
V
V
F
F
Q
Q
E
E
N
N
350
|
S
S
R
R
V
V
I
I
V
V
M
M
T
T
T
T
K
K
E
E
360
|
V
V
E
E
R
R
G
G
K
K
S
S
K
K
C
C
V
V
K
K
370
|
Y
Y
W
W
P
P
D
D
E
E
Y
Y
A
A
L
L
K
K
E
E
380
|
Y
Y
G
G
V
V
M
M
R
R
V
V
R
R
N
N
V
V
K
K
390
|
E
E
S
S
A
A
A
A
H
H
D
D
Y
Y
T
T
L
L
R
R
400
|
E
E
L
L
K
K
L
L
S
S
K
K
V
V
G
G
Q
Q
G
G
410
|
N
N
T
T
E
E
R
R
T
T
V
V
W
W
Q
Q
Y
Y
H
H
420
|
F
F
R
R
T
T
W
W
P
P
D
D
H
H
G
G
V
V
P
P
430
|
S
S
D
D
P
P
G
G
G
G
V
V
L
L
D
D
F
F
L
L
440
|
E
E
E
E
V
V
H
H
H
H
K
K
Q
Q
E
E
S
S
I
I
450
|
M
M
D
D
A
A
G
G
P
P
V
V
V
V
V
V
H
H
C
C
460
|
S
S
A
A
G
G
I
I
G
G
R
R
T
T
G
G
T
T
F
F
470
|
I
I
V
V
I
I
D
D
I
I
L
L
I
I
D
D
I
I
I
I
480
|
R
R
E
E
K
K
G
G
V
V
D
D
C
C
D
D
I
I
D
D
490
|
V
V
P
P
K
K
T
T
I
I
Q
Q
M
M
V
V
R
R
S
S
500
|
Q
Q
R
R
S
S
G
G
M
M
V
V
Q
Q
T
T
E
E
A
A
510
|
Q
Q
Y
Y
R
R
F
F
I
I
Y
Y
M
M
A
A
V
V
Q
Q
520
|
H
H
Y
Y
I
I
E
E
T
T
L
L
Click to Show/Hide the Structure
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
Click to Show/Hide the Resistance Disease of This Class
Acute myeloid leukemia [ICD-11: 2A60]
Click to Show/Hide
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
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
Liver cancer [ICD-11: 2C12]
Click to Show/Hide
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
Molecule expression in the normal tissue adjacent to the diseased tissue of patients
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Molecule expression in tissue other than the diseased tissue of patients
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the normal section of the tissue adjacent to the disease section
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
Download Molecule expression data in the tissue of the other disease section
Tissue-specific Molecule Abundances in Healthy Individuals
Click to Show/Hide the Molecule Abundances
Download the Tissue-Specific Variation(s) Profile
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 Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer. J Cancer. 2023 May 29;14(9):1592-1604.
Ref 6 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.

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