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FLASH GENE
Symbol PTPN11 contributors: mct/pgu - updated : 31-03-2016
HGNC name protein tyrosine phosphatase, non-receptor type 11
HGNC id 9644
Corresponding disease
DUP12Q24 chromosome 12q24.1q24.2 duplication
ECDM2 metachondromatosis 2
LEOPS Leopard syndrome
NGCS Noonan-like/multiple giant cell lesion syndrome
NS1 Noonan syndrome 1
Location 12q24.13      Physical location : 112.856.535 - 112.947.716
Synonym name
  • protein tyrosine phosphatase 2C
  • Src homology 2 domain- containing tyrosine phosphatase 2
  • Synonym symbol(s) PTP-1D, PTP2, PTP2C, PTP3, SHP2, CFC, CFC, BPTP3, SH-PTP2, SH-PTP3, MGC14433
    EC.number 3.1.3.48
    DNA
    TYPE functioning gene
    STRUCTURE 91.18 kb     16 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map cen - D12S2353 - D12S2246 - D12S2261 - D12S2310 - D12S2230 - D12S2289 - D12S2243 - D12S2269 - D12S2352 - D12S2259 - D12S1304 - D12S2352 - PTPN11 - D12S821 - D12S2273 - D12S2244 - D12S2249 - D12S2258 - D12S2311 - D12S2235 - D12S2296 - qter
    Physical map
    MYL2 12q23-q24.3 myosin, light polypeptide 2, regulatory, cardiac, slow CUTL2 12q24.12 cut-like 2 (Drosophila) FLJ32356 12q24.13 hypothetical protein FLJ32356 LNK 12q24 hypothetical protein FLJ32356 SCA2 12q24.1 spinocerebellar ataxia 2 (olivopontocerebellar ataxia 2, autosomal dominant, ataxin 2) BRAP 12q24 BRCA1 associated protein MGC5601 12q24.13 hypothetical protein MGC5601 ALDH2 12q24.2 aldehyde dehydrogenase 2 family (mitochondrial) FLJ39616 12q24.13 apoptosis-related protein PNAS-1 MAPKAPK5 12q24.12 mitogen-activated protein kinase-activated protein kinase 5 ADAM1 12q24.13 a disintegrin and metalloproteinase domain 1 (fertilin alpha) pseudogene LOC89894 12q24.13 hypothetical protein BC000282 C12orf8 12q24.13 chromosome 12 open reading frame 8 FLJ13089 12q24.13 hypothetical protein FLJ13089 FLN29 12q FLN29 gene product FLJ30092 12q24.13 AF-1 specific protein phosphatase FLJ34154 12q24.13 hypothetical protein FLJ34154 RPL6 12q23-q24.1 ribosomal protein L6 PTPN11 12q24.1 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1) RPH3A 12q24.11 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1) OAS1 12q24.2 2',5'-oligoadenylate synthetase 1, 40/46kDa OAS3 12q24.1 2'-5'-oligoadenylate synthetase 3, 100kDa OAS2 12q24.2 2'-5'-oligoadenylate synthetase 2, 69/71kDa DTX1 12q24.1 deltex homolog 1 (Drosophila) RASAL1 12q23-q24 RAS protein activator like 1 (GAP1 like) LOC387885 12 LOC387885 DDX54 12q24.21 DEAD (Asp-Glu-Ala-Asp) box polypeptide 54 FLJ14827 12q24.21 hypothetical protein FLJ14827 LOC115811 12q24.21 hypothetical protein BC013151 TPCN1 12q24.21 two pore segment channel 1 FLJ22233 LOC196463 12q24.21 hypothetical protein LOC196463 SDS 12q24.1 serine dehydratase SDS-RS1 12q24.21 serine dehydratase related sequence 1 LHX5 12q24.31-q24.32 LIM homeobox protein 5 KIAA0682 12q23.3-q24.2 LIM homeobox protein 5
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    16 - 6300 67.9 593 - 2007 17717529
    containing a different 3' end region
    - splicing 2069 52.7 460 - -
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   predominantly
    Endocrineparathyroid   moderately
     thyroid   highly
    Nervousbrain   predominantly
    Reproductivefemale systemovary  moderately
    Visualeyeretina    Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    VisualMuller cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES Hydrophilic
    STRUCTURE
    motifs/domains
  • two tandems SH2 domains (at the N terminus), functioning as phospho-tyrosine binding domains and mediating the interaction of this PTP with its substrates
  • a single protein tyrosine phosphatase catalytic domain
  • an ATP/GTP binding sequence
  • a C terminal hydrophilic tail
  • two tyrosyl phosphorylation sites
  • a Thr (Thr466) at the signature motif, critical for the catalytic activity
  • HOMOLOGY
    interspecies homolog to Drosophila corkscrew
    ortholog to rattus Ptpn11
    ortholog to murine Ptpn11
    intraspecies homolog to PTPN6
    Homologene
    FAMILY
  • protein-tyrosine phosphatase family
  • non-receptor class 2 subfamily
  • CATEGORY enzyme , signaling
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    text
  • required for full activation of RAS-Erk signaling in the cytoplasm and is also present in the nucleus, where it promotes Wnt target gene activation through dephosphorylation of parafibromin
  • basic FUNCTION
  • involved in intracellular signal transduction in response to PDGF, EGF, insulin
  • inhibiting interleukin 6 signal transduction
  • catalytic activity required for FGF2-induced Ca2+ mobilization
  • plays an essential role in IL3 signal transduction in both catalytic-dependent and -independent manners
  • plays diverse roles in signal transduction including signaling via the RAS-mitogen activated protein kinase (MAPK) pathway
  • tyrosine phosphatase which functions as a positive regulator downstream of RTKs, activating growth-stimulatory signalling pathways
  • playing an essential role in normal hematopoiesis and inducing aberrant hyperactivation of the Ras-Erk pathway
  • modulates and regulates signaling through numerous pathways, many of which are active in the developing endocardial cushions and implicated the ERK pathway as a central mechanism
  • mediates dephosphorylation of ROCK2 and, therefore, regulates RhoA-induced cell rounding, indicating that it couples with RhoA signaling to control ROCK2 activation during deadhesion
  • having a role in adhesion-dependent activation of the RhoA family small GTPases
  • promotes HER2-induced signaling and transformation at least in part by dephosphorylating a negative regulatory autophosphorylation site
  • regulates tyrosine phosphorylation of NEDD9, hence opposing the effect of kinases, and is a negative regulator of cell migration mediated by NEDD9 (
  • involved in the SEMA4D-signaling in the developing nervous system
  • regulating myogenesis by coupling to PTK2 signaling pathway
  • PTPN11-mediated Ras-mitogen-activated protein kinase (Ras-MAPK) signaling plays a critical role in Müller cell maturation and function, which is necessary for the survival of retinal neurons
  • role in controlling Ras signaling, and retinal degeneration caused by aberrant receptor tyrosine kinase (RTK)-Shp2 signaling may be prevented by direct intervention in the Ras-MAPK pathway
  • its signaling may play equally important roles in retinal survival in both physiological and pathological conditions
  • governs the opposing functions of parafibromin, deregulation of which may cause the development of tumors or developmental malformations)
  • important role in STAT5 activation and growth factor -mediated proliferation, survival, and differentiation of human progenitor cells
  • required for induction of CEBPA expression and granulopoiesis in response to CSF3 or other cytokines independent of PTPN11-mediated ERK activation
  • positive role in the activation of the RAS/MAPK ERK1/2 pathway
  • positively regulates GH-evoked ERK activation, possibly through its catalytic activity
  • is required for efficient recovery of cell–cell junctions and for restoration of the endothelial barrier function
  • SHP2 also promotes the mobility of CDH5 in the plasma membrane, stimulating the reassembly of adherens junctions, the closure of intercellular gaps, and restoration of endothelial integrity
  • role for PTPN11 as a nutrient-sensing regulator in skeletal myoblasts that is required for the activation of RPS6KB1
  • involvement in regulating the focal adhesions (FAs) and the cytoskeleton for force maintenance and organization
  • playing an important role in determining the mechanical polarity in cellular response to matrix rigidity
  • regulates focal adhesion kinase to promote EGF-induced lamellipodia persistence and cell migration
  • widely expressed protein tyrosine phosphatase required for signal transduction from multiple cell surface receptors
  • is essential for spermatogonial stem cells (SSCs) to maintain fertility and the pathogenesis of infertility in humans with PTPN11 mutations is due to compromised SSC functions that block spermatogenesis
  • FRS2-PTPN11 complex is the key mediator of FGF signaling in lens development
  • promotes the invasion and metastasis of oral cancer cells
  • involved in the process of EMT and HOOK1 repressed EMT by regulating the activation of PTPN11
  • promotes activation of RAS-Erk and PI3K-AKT1 and is crucial for hematopoietic cell function
  • its phosphatase function positively regulates CLEC7A- and TDGF1P3-stimulated ROS production in macrophages by dephosphorylating and thus mitigating the inhibitory function of SIRPA and by promoting Erk activation
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction , sensory transduction/hearing
    a component
  • PDGFRB and modulating its Tyr 771 phosphorylation, thereby controlling Ras GAP recruitment and Ras/MAP kinase signaling in the heterodimeric configuration of PDGFR
  • PECAM1/PTPN11 complexes, formed in a LYN-dependent manner, suppress GP6 signaling
  • PTPN11 forms an enzyme–substrate complex with CTNNB1
  • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP
  • protein
  • protein zero related (PZR) for cell signaling
  • PTPNS1
  • GAB1
  • phosphorylated LIME1
  • phosphorylated SIT1
  • interacting with SEMA4D (PTPN11-mediated tyrosine dephosphorylation is an important step in SEMA4D-induced axon repulsion
  • interacting with STAT3 (STAT3 is a direct target for PTPN11 and is potentially an essential signaling component in PTPN11 mutation-associated Noonan Syndrome and Juvenile Myelomonocytic Leukemia)
  • COASY is a novel potential substrate of PTPN11
  • SIGLEC12 binds to the tyrosine phosphatases PTPN6 and PTPN11 in a phosphorylation-dependent manner
  • dephosphorylates parafibromin/CDC73, a core component of the RNA polymerase II-associated factor (PAF) complex
  • is required for induction of CEBPA expression and granulopoiesis in response to G-CSF or other cytokines independent of PTPN11-mediated ERK activation 8)
  • interaction with ACSL4 (involvement of PTPN11 activity in the regulation of the expression of the fatty acid-metabolizing enzyme ACSL4)
  • PTPN11 acts via ROCK2 to regulate the cardiac actin cytoskeleton
  • negatively regulates GH-induced IGF1 release through a RAS/ERK-dependent mechanism
  • participates in GH-induced RAS/ERK1/2 activation by dephosphorylating GAB1 on its RASA1 binding sites
  • is required for leucine-induced activation of RPS6KB1 in skeletal myoblasts
  • controls the recovery of endothelial barrier function by dephosphorylating CTNNB1 and promoting the mobility of CDH5 at the plasma membrane
  • GRB2 controls FGFR2 signaling by regulating receptor kinase and PTPN11 phosphatase activity in the absence of extracellular stimulation
  • physically interacts with transcriptional coactivators YAP1 and TAZ, targets of the cell-density-sensing Hippo signal
  • HOOK1 was an endogenous negative regulator of PTPN11 phosphatase activity
  • protein-protein interaction between CAV1 and PTPN11 is dependent on the N-SH2 domain of PTPN11
  • PDCD1 blocked NFKB1-dependent cytokine release in a PTPN11-dependent manner
  • cell & other
  • erythrocyte SLC4A1 (band 3) protein
  • REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) NS1 , LEOPS , NGCS , DUP12Q24 , ECDM2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in severe congenital neutropenia (defective dephosphorylation of proteins involved in signaling pathways)
    tumoral somatic mutation     gain of function
    gain of function, in juvenile leukemia, myelomonocytic, rhabdomyosarcoma, myelodysplastic syndrome, acute myeloid leukemia (high phosphatase activity observed in mutations at codons 61, 71, 72, and 76 significantly associated with leukemogenesis) and rarely in solid tumors
    tumoral somatic mutation      
    in high hyperdiploid childhood acute lymphoblastic leukemia
    tumoral germinal mutation     gain of function
    activating mutations in 3.4p100 of neuroblastomas
    constitutional     --low  
    specifically disrupted extracellular signal-regulated kinase (ERK) signaling in Müller cells, leading to STAT3 activation in photoreceptors
    Susceptibility to cancer
    Variant & Polymorphism other
  • risk for developing cancer is 3.5-fold increased risk compared with that in the general population
  • Candidate gene
    Marker
  • positive PTPN11 and UGP2 expression correlated with clinicopathological and biological behaviors, and poor-prognosis of gallbladder cancer
  • Therapy target
    SystemTypeDisorderPubmed
    cancerreproductivebreast
    might serve as a therapeutic target against breast cancer and other cancers characterized by HER2 overexpression
    mental retardation  
    ANIMAL & CELL MODELS
  • selective deletion of Shp2, in striated muscle results in severe dilated cardiomyopathy in mice, leading to heart failure and premature mortality
  • LEOPARD syndrome mutations in PTPN11 gene have gain-of-function effects during Drosophila development; transgenic Drosophila expressing the two commonest LS mutations in csw under control of UAS/GAL4 system, ubiquitous expression of those LS-causing alleles resulted in a gain-of-function phenotype, which was similar to that of the Noonan transgenic flies
  • decreased Igf1 levels in Ptpn11-mutated mice suggesting an involvement of Shp2 in GH signaling
  • germline mutation Shp2D61G in animal models enhances hematopoietic stem cell activity and induces myeloproliferative disease