PTPN11 (Protein tyrosine phosphatase, non-receptor type, 11)

2005-02-01   Marco Tartaglia  , Bruce D Gelb  

Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanitö, Rome, Italy

Identity

HGNC
LOCATION
12q24.13
LOCUSID
ALIAS
BPTP3,CFC,JMML,METCDS,NS1,PTP-1D,PTP2C,SH-PTP2,SH-PTP3,SHP2
FUSION GENES

DNA/RNA

Description

The PTPN11 gene is divided in 16 exons. Exon 1 contains the 5 untranslated region and the translation initiation ATG, and a few additional codons. Exon 15 contains the stop codon and exon 16 contains a major portion of the 3 untranslated region. Other features of the PTPN11 gene, such as the promoter region and enhancer elements have not been delineated.

Transcription

A 7.0-kb transcript is detected in several tissues (heart, brain, lung, liver, skeletal muscle, kidney, and pancreas) with highest steady-state levels in heart and skeletal muscle. The predominant human PTPN11 mRNA contains an open reading frame of 1,779 bases, resulting in a predicted protein of 593 amino acid residues. A second mRNA containing 12 additional base pairs (exon 11) has been identified. Little additional information is available about this alternative transcript.

Pseudogene

A number of PTPN11-related processed pseudogenes, i.e. with no apparent exon structure, have been documented in the human genome. All the pseudogenes share >92% nucleotide identity with the PTPN11 cDNA (including the 5-UTR and 3-UTR), but harbour frameshift mutations and multiple stop codons. Three of the five pseudogenes appear to be expressed with distinct tissue distributions and expression levels.

Proteins

Atlas Image
PTPN11 genomic organization and SHP-2 domain structure:
Figure 1 : (A) The PTPN11 gene and SHP-2 domain characterization. The coding exons are shown as numbered filled boxes. The functional domains of the protein, comprising two tandemly arranged SH2 domains at the N terminus (N-SH2 and C-SH2) followed by a protein tyrosine phosphatase (PTP) domain, are shown below. Numbers below the domain structure indicate the amino-acid boundaries of those domains. (B) Three-dimensional structure of SHP-2 in its catalytically inactive conformation, as determined by Hof et al. (1998). Residues involved in catalysis are shown (space fill).
Figure 2 : Location of SHP-2 mutated residues in human disease. (A) Noonan syndrome and LEOPARD syndrome (germ-line origin; N=224); (B) Noonan syndrome with juvenile myelomonocytic leukemia (germ-line origin; N=11); (C) hematologic malignancies, including juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia (somatic origin; N=97). The pictures show the C trace of SHP-2 in its catalytically inactive conformation. Affected residues are indicated with their side chains as black sticks.

Description

SHP-2 is a member of a small subfamily of cytoplasmic Src homology 2 (SH2) domain-containing protein tyrosine phosphatases. Both the N-SH2 and C-SH2 domains selectively bind to short amino acid motifs containing a phosphotyrosyl residue and promote SHP-2 association with activated receptors and other signaling partners. Crystallographic data indicate that the N-SH2 domain also interacts with the PTP domain using a separate site. As these subdomains show negative cooperativity, the N-SH2 domain functions as an intramolecular switch controlling SHP-2 catalytic activation. Specifically, the N-SH2 domain interacts with the PTP domain basally, blocking the catalytic site. Binding of the N-SH2 phosphopeptide-binding site to the phosphotyrosyl ligand promotes a conformational change of the domain that weakens the auto-inhibiting intramolecular interaction, making the catalytic site available to substrate, thereby activating the phosphatase.

Expression

Widely expressed in both embryonic and adult tissues.

Localisation

Cytoplasmic. It binds to activated cell surface receptors, cell adhesion molecules and scaffolding adapters.

Function

SHP-2 functions as an intracellular signal transducer. It positively modulates signal flow in most circumstances, but can also function as negative regulator depending upon its binding partner and interactions with downstream signaling networks. SHP-2 positively controls the activation of the RAS/MAPK cascade induced by several growth factors, and negatively regulates JAK/STAT signaling. In most cases, SHP-2s function in intracellular signaling appears to be immediately proximal to activated receptors and upstream to RAS. The mechanisms of SHP-2s action and its physiological substrates are still poorly defined. However, both membrane translocation and PTPase activity are required for SHP-2 function. SHP-2 is required during development. Embryos nullizygous for Shp-2 have defects in gastrulation and mesodermal patterning resulting in severe abnormalities in axial and paraxial mesodermal structures. Shp-2 function is also required for development of terminal and skeletal structures, semilunar valvulogenesis in the heart, and hematopoiesis.

Homology

PTPN6 (protein tyrosine phosphatase, non-receptor type, 6) previously known as SHP1 or SHP-1 (Src homology 2 domain-containing protein tyrosine phosphatase, 1).

Mutations

Note

At least two distinct classes of PTPN11 mutations have been identified in humans.
  • The first group, which has germ-line origin, causes Noonan syndrome and closely related developmental disorders.
  • The second group, acquired as a somatic event, has been documented in a heterogeneous group of hematologic malignancies and pre-leukemic disorders, and rarely in certain solid tumors.
    The vast majority of mutations affect residues residing at or close to the interface between the N-SH2 and PTP domains. Increasing evidence supports that both germ-line and somatic mutations promote SHP-2 gain-of-function by destabilizing the catalytically inactive conformation of the protein, and prolong signal flux through the RAS/MAPK pathway in a ligand-dependent manner.
    A mouse model bearing the NS-causative D61G mutation in the Ptpn11 gene has been recently generated and characterized. The Ptpn11D61G/D61G genotype is embryonic lethal. At day E13.5, these embryos are grossly edematous and hemorrhagic, have diffuse liver necrosis and severe cardiac defects. Heterozygous embryos exhibit cardiac defects, proportionate growth failure and perturbed craniofacial development. Hematologic anomalies include a mild myeloproliferative disease. Ptpn11D61G/+ embryonic fibroblasts exhibit a three-fold increased Shp-2 activity and increased association of Shp-2 with Gab1 after stimulation with EGF. Cell culture and whole embryo studies reveal that increased RAS/MAPK signaling is variably present, appearing to be cell-context specific.
  • Germinal

    Selection: 124A>G (T42A), 179-181delGTG (delGly60), 181-183delGAT (delAsp61), 182A>G (D61G), 184T>G (Y62D), 188A>G (Y63C), 214G>T (A72S), 215C>G (A72G), 218C>T (T73I), 228G>T,C (E76D), 236A>G (N79R), 317A>C (D106A), 836A>G (Y279C), 922A>G (N308D), 1403C>T (T468M), 1510A>G (M504V).

    Somatic

    Selection: 181G>T (D61Y), 182A>T (D61V), 205G>A (E69K), 211-213TTT>AAA (F71K), 214G>A (A72T), 215C>T (A72V), 226G>A (E76K), 226G>C (E76Q), 227A>T (E76V), 227A>G (E76G), 227A>C (E76A), 1471C>T (P491S), 1472C>T (P491L), 1504T>C (S502P), 1504T>G (S502A), 1520C>A (T507K), 1528C>A (Q510K).

    Implicated in

    Entity name
    Noonan syndrome, Noonan-like/multiple giant cell lesion syndrome and LEOPARD syndrome.
    Note
    Germ-line origin. Gain-of-function mutations. Increased basal protein tyrosine phosphatase activity. Prolonged ligand-dependent activation of the RAS/MAPK cascade.
    Disease
    Noonan syndrome is a genetically heterogeneous and clinically variable developmental disorder defined by short stature, facial dysmorphism and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, down-slanting palpebral fissures, ptosis, high-arched palate and low-set, posteriorly rotated ears. Cardiovascular abnormalities, primarily pulmonic stenosis and hypertrophic cardiomyopathy, are present in up to 85% of affected individuals. Additional relatively frequent features are multiple skeletal defects, webbed neck, mental retardation, cryptorchidism and bleeding diathesis. Children with Noonan syndrome are predisposed to a spectrum of hematologic abnormalities, including transient monocytosis, thrombocytopenia and rarely juvenile myelomonocytic leukemia and acute leukemia.
    Entity name
    Juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, melanoma, neuroblastoma, lung adenocarcinoma, colon cancer.
    Note
    Somatic origin.
    Prognosis
    No data are currently available.
    Oncogenesis
    Gain-of-function mutations. Increased basal protein tyrosine phosphatase activity. Prolonged ligand-dependent activation of the RAS/MAPK cascade.

    Article Bibliography

    Pubmed IDLast YearTitleAuthors

    Other Information

    Locus ID:

    NCBI: 5781
    MIM: 176876
    HGNC: 9644
    Ensembl: ENSG00000179295

    Variants:

    dbSNP: 5781
    ClinVar: 5781
    TCGA: ENSG00000179295
    COSMIC: PTPN11

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000179295ENST00000351677Q06124
    ENSG00000179295ENST00000392597Q06124
    ENSG00000179295ENST00000530818H0YF12
    ENSG00000179295ENST00000635625Q06124
    ENSG00000179295ENST00000635652A0A0U1RRI0
    ENSG00000179295ENST00000639857A0A1W2PPU4

    Expression (GTEx)

    0
    50
    100
    150

    Pathways

    PathwaySourceExternal ID
    Axon guidanceKEGGko04360
    Jak-STAT signaling pathwayKEGGko04630
    Natural killer cell mediated cytotoxicityKEGGko04650
    Leukocyte transendothelial migrationKEGGko04670
    Adipocytokine signaling pathwayKEGGko04920
    Epithelial cell signaling in Helicobacter pylori infectionKEGGko05120
    Renal cell carcinomaKEGGko05211
    Chronic myeloid leukemiaKEGGko05220
    Axon guidanceKEGGhsa04360
    Jak-STAT signaling pathwayKEGGhsa04630
    Natural killer cell mediated cytotoxicityKEGGhsa04650
    Leukocyte transendothelial migrationKEGGhsa04670
    Adipocytokine signaling pathwayKEGGhsa04920
    Epithelial cell signaling in Helicobacter pylori infectionKEGGhsa05120
    Renal cell carcinomaKEGGhsa05211
    Chronic myeloid leukemiaKEGGhsa05220
    Neurotrophin signaling pathwayKEGGko04722
    Neurotrophin signaling pathwayKEGGhsa04722
    Herpes simplex infectionKEGGko05168
    Herpes simplex infectionKEGGhsa05168
    Proteoglycans in cancerKEGGhsa05205
    Proteoglycans in cancerKEGGko05205
    Ras signaling pathwayKEGGhsa04014
    DiseaseREACTOMER-HSA-1643685
    Diseases of signal transductionREACTOMER-HSA-5663202
    PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
    Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
    Immune SystemREACTOMER-HSA-168256
    Adaptive Immune SystemREACTOMER-HSA-1280218
    Costimulation by the CD28 familyREACTOMER-HSA-388841
    CTLA4 inhibitory signalingREACTOMER-HSA-389513
    PD-1 signalingREACTOMER-HSA-389948
    Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
    Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
    PIP3 activates AKT signalingREACTOMER-HSA-1257604
    Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
    Innate Immune SystemREACTOMER-HSA-168249
    Toll-Like Receptors CascadesREACTOMER-HSA-168898
    Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
    MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
    TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
    Activation of IRF3/IRF7 mediated by TBK1/IKK epsilonREACTOMER-HSA-936964
    Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
    Activated TLR4 signallingREACTOMER-HSA-166054
    DAP12 interactionsREACTOMER-HSA-2172127
    DAP12 signalingREACTOMER-HSA-2424491
    Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
    Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
    Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
    Interferon SignalingREACTOMER-HSA-913531
    Interferon alpha/beta signalingREACTOMER-HSA-909733
    Regulation of IFNA signalingREACTOMER-HSA-912694
    Interferon gamma signalingREACTOMER-HSA-877300
    Regulation of IFNG signalingREACTOMER-HSA-877312
    Signaling by InterleukinsREACTOMER-HSA-449147
    Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
    Interleukin-6 signalingREACTOMER-HSA-1059683
    Prolactin receptor signalingREACTOMER-HSA-1170546
    HemostasisREACTOMER-HSA-109582
    Platelet homeostasisREACTOMER-HSA-418346
    Platelet sensitization by LDLREACTOMER-HSA-432142
    Platelet activation, signaling and aggregationREACTOMER-HSA-76002
    GPVI-mediated activation cascadeREACTOMER-HSA-114604
    Cell surface interactions at the vascular wallREACTOMER-HSA-202733
    Tie2 SignalingREACTOMER-HSA-210993
    PECAM1 interactionsREACTOMER-HSA-210990
    Signal TransductionREACTOMER-HSA-162582
    Signaling by EGFRREACTOMER-HSA-177929
    GAB1 signalosomeREACTOMER-HSA-180292
    Signaling by FGFRREACTOMER-HSA-190236
    Signaling by FGFR1REACTOMER-HSA-5654736
    Downstream signaling of activated FGFR1REACTOMER-HSA-5654687
    FRS-mediated FGFR1 signalingREACTOMER-HSA-5654693
    PI-3K cascade:FGFR1REACTOMER-HSA-5654689
    Negative regulation of FGFR1 signalingREACTOMER-HSA-5654726
    Spry regulation of FGF signalingREACTOMER-HSA-1295596
    Signaling by FGFR2REACTOMER-HSA-5654738
    Downstream signaling of activated FGFR2REACTOMER-HSA-5654696
    FRS-mediated FGFR2 signalingREACTOMER-HSA-5654700
    PI-3K cascade:FGFR2REACTOMER-HSA-5654695
    Negative regulation of FGFR2 signalingREACTOMER-HSA-5654727
    Signaling by FGFR3REACTOMER-HSA-5654741
    Downstream signaling of activated FGFR3REACTOMER-HSA-5654708
    FRS-mediated FGFR3 signalingREACTOMER-HSA-5654706
    PI-3K cascade:FGFR3REACTOMER-HSA-5654710
    Negative regulation of FGFR3 signalingREACTOMER-HSA-5654732
    Signaling by FGFR4REACTOMER-HSA-5654743
    Downstream signaling of activated FGFR4REACTOMER-HSA-5654716
    FRS-mediated FGFR4 signalingREACTOMER-HSA-5654712
    PI-3K cascade:FGFR4REACTOMER-HSA-5654720
    Negative regulation of FGFR4 signalingREACTOMER-HSA-5654733
    Signaling by Insulin receptorREACTOMER-HSA-74752
    Insulin receptor signalling cascadeREACTOMER-HSA-74751
    IRS-mediated signallingREACTOMER-HSA-112399
    PI3K CascadeREACTOMER-HSA-109704
    Signalling by NGFREACTOMER-HSA-166520
    NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
    PI3K/AKT activationREACTOMER-HSA-198203
    Signaling by PDGFREACTOMER-HSA-186797
    Downstream signal transductionREACTOMER-HSA-186763
    Signaling by SCF-KITREACTOMER-HSA-1433557
    MAPK family signaling cascadesREACTOMER-HSA-5683057
    MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
    RAF-independent MAPK1/3 activationREACTOMER-HSA-112409
    MAPK3 (ERK1) activationREACTOMER-HSA-110056
    MAPK1 (ERK2) activationREACTOMER-HSA-112411
    Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
    IGF1R signaling cascadeREACTOMER-HSA-2428924
    IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
    Signaling by LeptinREACTOMER-HSA-2586552
    Cell-Cell communicationREACTOMER-HSA-1500931
    Signal regulatory protein (SIRP) family interactionsREACTOMER-HSA-391160
    Developmental BiologyREACTOMER-HSA-1266738
    Axon guidanceREACTOMER-HSA-422475
    Netrin-1 signalingREACTOMER-HSA-373752
    Netrin mediated repulsion signalsREACTOMER-HSA-418886
    Insulin resistanceKEGGhsa04931
    Phospholipase D signaling pathwayKEGGko04072
    Phospholipase D signaling pathwayKEGGhsa04072
    Interleukin-6 family signalingREACTOMER-HSA-6783589
    PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
    RET signalingREACTOMER-HSA-8853659
    Signaling by METREACTOMER-HSA-6806834
    MET activates PTPN11REACTOMER-HSA-8865999

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    References

    Pubmed IDYearTitleCitations
    376887672024Synergistic effects of BTN3A1, SHP2, CD274, and STAT3 gene polymorphisms on the risk of systemic lupus erythematosus: a multifactorial dimensional reduction analysis.1
    377863832024Progesterone and cAMP synergistically induce SHP2 expression via PGR and CREB1 during uterine stromal decidualization.0
    378471072024Clinical Variability in a Family with Noonan Syndrome with a Homozygous PTPN11 Gene Variant in Two Individuals.0
    379239382024Mutations in PTPN11 could lead to a congenital myasthenic syndrome phenotype: a Noonan syndrome case series.0
    382116822024Plasma-derived exosomal protein SHP2 deficiency induces neutrophil hyperactivation in Behcet's uveitis.1
    382519392024Single Ion Pair Is Essential for Stabilizing SHP2's Open Conformation.1
    383581852024High expression of SHP2 predicts a promising prognosis in colorectal cancer.0
    383946392024Macrophage SHP2 Deficiency Alleviates Diabetic Nephropathy via Suppression of MAPK/NF-κB- Dependent Inflammation.0
    385404042024Spectrum of Mutations in PTPN11 in Russian Cohort.0
    386570422024SHP2 regulates GluA2 tyrosine phosphorylation required for AMPA receptor endocytosis and mGluR-LTD.0
    389244322024MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by NF1 loss in Schwann cells and skeletal stem/progenitor cells.0
    389652232024SHP2 as a primordial epigenetic enzyme expunges histone H3 pTyr-54 to amend androgen receptor homeostasis.0
    376887672024Synergistic effects of BTN3A1, SHP2, CD274, and STAT3 gene polymorphisms on the risk of systemic lupus erythematosus: a multifactorial dimensional reduction analysis.1
    377863832024Progesterone and cAMP synergistically induce SHP2 expression via PGR and CREB1 during uterine stromal decidualization.0
    378471072024Clinical Variability in a Family with Noonan Syndrome with a Homozygous PTPN11 Gene Variant in Two Individuals.0

    Citation

    Marco Tartaglia ; Bruce D Gelb

    PTPN11 (Protein tyrosine phosphatase, non-receptor type, 11)

    Atlas Genet Cytogenet Oncol Haematol. 2005-02-01

    Online version: http://atlasgeneticsoncology.org/gene/41910/case-report-explorer/gene-fusions-explorer/favicon/favicon-32x32.png