Database for Annotation, Visualization and Integrated Discovery 2.1
National Institute of Allergy and Infectious Disease
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protein tyrosine phosphatase, non-receptor type 11(PTPN11) protein tyrosine phosphatase, non-receptor type 11(PTPN11) Related Genes Homo sapiens
CHROMOSOME 12, 3, 4,
CYTOBAND 12q24, 3q13.12, 4q21.22,
ENSEMBL_GENE_ID ENSG00000179295,
GENERIF_SUMMARY upon translocation, CagA perturbs cellular functions by deregulating SHP-2, SHP-2 modulates phosphorylation of PDGF receptors, thereby controls RasGTP recruitment and Ras/MAP kinase signaling in the heterodimeric configuration of the PDGF receptors, Specific SHP-2 partitioning in raft domains triggers integrin-mediated signaling via Rho activation, interacts with siglec-11, PTPN11 mutations in Noonan syndrome, Band 3 is an anchor protein for and a target for SHP-2 tyrosine phosphatase in human erythrocytes., PTPN11 mutations are responsible for Noonan syndrome in a substantial fraction of patients and that relatively infrequent features of Noonan syndrome, such as sensory deafness and bleeding diathesis, can also result from mutations of PTPN11., Some PTPN11 mutations (e.g., Y279C) are associated with both the Noonan syndrome phenotype and with skin pigmentation anomalies, such as multiple lentigines or cafe au lait spots (LEOPARD syndrome)., SHP-2 is a dual-specificity protein phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues and plays an important role in modulating STAT function in gene regulation, Mutations in PTPN11/SHP2 underlie a common form of Noonan syndrome and confirm that the disease exhibits both allelic and locus heterogeneity., Results indicate that Gab1 and SHP-2 promote the undifferentiated epidermal cell state by facilitating Ras/MAPK signaling., absence of mutation in cases of cardiofaciocutaneous syndrome, activation state of alphaVbeta3 integrin is an important regulator of the duration of insulin-like growth factor I receptor phosphorylation and this regulation is mediated through changes in the subcellular localization of SHP-2, These data suggest, that there are two, largely distinct modes of negative regulation of gp130 activity, despite the fact that both SOCS3 and SHP2 are recruited to the same site within gp130., We sequenced the entire coding region of the PTPN11 gene in ten well-characterised CFC patients and found no base changes. We also studied PTPN11 cDNA in our patients and demonstrated that there are no interstitial deletions either., SHP-2 may function as an adaptor molecule downstream of the the prolactin receptor and highlight a new recruitment mechanism of SHP-2 substrates., SHP2 positively regulates IL-2 induced MAPK activation in malignant T cells. SHP2 may not be involved in the activation of Stat3 or Stat5 in cutaneous T-cell lymphoma cells., The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa, During platelet activation, a functionally active complex between SHIP-2, filamin, actin, and GPIb-IX-V may orchestrate the localized hydrolysis of PtdIns(3,4,5)P3 and thereby regulate cortical and submembraneous actin., SHP-2 catalytic activity plays a direct role in the inhibitory function of killer cell Ig-like receptors, and SHP-2 inhibits NK cell activation in concert with SHP-1., Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia., PTPN11 mutations do not cause Costello syndrome, Required for RetM918T-induced Akt activation. Downstream mediator of mutated receptors RetC634Y and RetM918T. Acts as limiting factor in Ret-associated endocrine tumors, in neoplastic syndromes multiple endocrine neoplasia types 2A and 2B., SHP-2 has a role as a positive regulator of cytokine receptor signaling by regulating ubiquitination/degradation pathways, SHP-2 is an important cellular PTPase that is mutated in myeloid malignancies, results reveal that Gab1 protein recruits SHP2 protein tyrosine phosphatase to dephosphorylate paxillin, SHP-2/Gab1 association is critical for linking EGFR to NF-kappaB transcriptional activity via the PI3-kinase/Akt signaling axis in glioblastoma cells, wider role of PTPN11 lesions in leukemogenesis, but also a lineage-related and differentiation stage-related contribution of these lesions to clonal expansion., A missense mutation (836A-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in the patient with LEOPARD syndrome, whereas no mutation in PTPN11 gene was detected in the father or in additional family members, inhibition of NK cell cytotoxicity by KIR2DL5 was blocked by dominant-negative SHP-2, but not dominant-negative SHP-1, whereas both dominant-negative phosphatases can block inhibition by KIR3DL1., PTPN11 mutations account for approximately 40% of Noonan syndrome patients. Type of cardiovascular lesions and occurrence of hematological abnormalities are different in mutation-positive and mutation-negative patients., In contrast to childood MDS and AML, mutations in PTPN11 make little or no contribution to the pathogenesis of adult MDS and AML., PTPN11 missense mutations are associated with acute myeloid leukemia, Aspartate 61 plays a major role for proper down-regulation of the protein tyrosine phosphatase activity of SHP-2; the D61Del variant is predicted to have lower stability of the D'EF loop of the N-terminal SH2 domain compared to the wild-type, Most common mutation was A922G in exon 8. In exon 4 a mutation encoded C-SH2 domain of PTPN11 gene in two patients. A 218C-->T mutation was found in exon 3 in a patient with Noonan syndrome and mild juvenile myelomonocytic leukaemia., SHP2 binds CAT and acquires a hydrogen peroxide-resistant phosphatase activity via integrin-signaling., SHP-2 has a role in regulating IL-1-induced Ca2+ flux and ERK activation via phosphorylation of PLCgamma1, data support the hypothesis that PTPN11 mutations induce hematopoietic progenitor hypersensitivity to GM-CSF due to hyperactivation of the Ras signaling axis, Tyr-992 and Tyr-1173 are required for phosphorylation of the epidermal growth factor receptor by ionizing radiation and modulation by SHP2, Mutations are rare in adult myelodysplastic syndromes and chronic myelomonocytic leukemia., 10 genes were down-regulated following treatment of the T-ALL cells with 0.15 and 1.5 microg/mL of metal ores at 72 h, Pathogenesis of Noonan syndrome and leukemia is associated with enhanced phosphatase activity of mutant SHP-2, SHPS-1 functions as an anchor protein that recruits both Shc and SHP-2, whose recruitment is necessary for IGF-I-dependent Shc phosphorylation, data suggest a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with juvenile myelomonocytic leukemia, Noonan syndrome/myeloproliferative disease, and Noonan syndrome, Results show that PTPN11 mutations are rarely found in two isolated forms of congenital heart disease., PTPN11 mutations are rare in adult myeloid malignancies [review], Presence of PTPN11 mutations in patients with Noonan syndrome indicates a reduced growth response to long-term human growth hormone treatment., an important role for a PECAM1-SHP2-Tie2 pathway in flow-mediated signal transduction., SHP-2 mutations in Noonan syndrome cause mild GH resistance by postreceptor signaling defect, partially compensated for by elevated GH secretion. May contribute to short stature phenotype in children with SHP-2 mutations and poor response to rhGH., Modeling analyses show that different SHP2 mutants can affect basal activation, SH2 domain-phosphopeptide affinity, and/or substrate specificity to varying degrees., aberrantly increased expression of Shp2 may contribute, collaboratively with other factors, to leukemogenesis, Missense mutations and the role of SHP-2 in signal transduction, development and hematopoiesis, as well as on the consequences of SHP-2 gain-of-function. Review., cardiovascular anomalies and hematologic abnormalities are predominant in mutation positive patients, SHP-2 tyrosine phosphorylation on residue Y542 promoted IL-1beta mediated focal adhesion maturation., SHP-2 recruitment to p85 is required for IGF-I-stimulated association of the p85/p110 complex with insulin receptor substrate-1 and for the subsequent activation of the PI-3 kinase pathway leading to increased cell migration, Type I collagen limits VEGFR-2 signaling by a SHP2 protein-tyrosine phosphatase-dependent mechanism 1., Inhibition of focal adhesion kinase by SHP-2 plays a crucial role in the morphogenetic activity of Helicobacter pylori CagA., Diversity of germline and somatic PTPN11 mutations were studied in Noonan syndrome, LEOPARD syndrome and leukemia., The phosphorylation of SHP-2 by GM-CSF promotes the binding of SHP-2 to the GM-CSF receptor to the disadvantage of CLECSF6., data suggests that mutations in the PTPN11 gene are not a cause of hypertrophic cardiomyopathy in the absence of Noonan/LEOPARD syndromes, A PTPN11 gene mutation (Y63C) causing Noonan syndrome is not associated with short stature in the general population., Our data suggest that mutations of PTPN11 as well as RAS play a role in the pathogenesis of not only myeloid hematological malignancies but also a subset of RMS malignancies, The clinical suspicion of LEOPARD syndrome may be confirmed by molecular screening for PTPN11 mutations., The PTPN11 protein mutation can be acquired during progression of myelodysplastic syndrome JMML., Recruitment of SHP2 to speicific sites of autophosphorylation contributes to FLT3-mediated Erk activation and proliferation., both SHP-1 and SHP-2 have a positive role in epidermal growth factor-induced ERK1/2 activation and they act cooperatively rather than antagonistically., Upon IGF-I stimulation, a complex assembles on SHPS-1 that contains SHP-2, c-Src, and Shc wherein Src phosphorylates Shc, a signaling step that is necessary for an optimal mitogenic response, Tyr-542 of SHP-2 modulates IL-1-induced Ca2+ signals and association of the ER with focal adhesions, ICSBP tyrosine phosphorylation is necessary for the activation of NF1 transcription. ICSBP is a substrate for SHP2 protein tyrosine phosphatase (SHP2-PTP)., Our results suggest that DCA differentially regulates focal adhesion complexes and that tyrosine phosphatase ShP2 has a role in DCA signaling., Mutation of the PTPN11 gene is the main causal factor in LEOPARD syndrome, and it also plays a role in neurofibromatosis-Noonan syndrome., uPAR expression of lung airway epithelial cells is regulated at the level of mRNA stability by inhibition of protein tyrosine phosphatase-mediated dephosphorylation of uPAR mRNA binding proteins and demonstrate that the process involves SHP2., 1226 G-->C causes amino acid substitution G409A and results in Noonan Syndrome. Mutations in this particular region of SHP-2 may have effects on the protein that differ from those of the classical mutations., PTPN11 as the first proto-oncogene that encodes a cytoplasmic tyrosine phosphatase with Shp2 domain; diseases caused by mutations; role in hematopoiesis, support the view that an increase in the affinity of SHP-2 for its binding partners, caused by destabilization of the closed, inactive conformation, The significance of exercise-induced alterations in cytosolic SHP2 and insulin-stimulated Akt pSer(473) on the improvement in insulin sensitivity requires further elucidation., This short review discusses the physiological role of Shp2 in the molecular switch governing embryonic stem cell self-renewal versus differentiation., Association of single tSNPs with both apoB and LDL cholesterol as well as interactions between the two genes suggest that variants influencing SHP-2 activity may modulate the acute pathway by which insulin regulates these lipids, novel mechanism regulating GH signaling in which estrogen receptor modulators enhance GH activation of the JAK2/STAT5 pathway in a cell-type-dependent manner by attenuating protein tyrosine phosphatase activities, An unselected series of 140 patients with therapy-related MDS or AML were investigated for mutations of PTPN11 in Exons 3, 4, 8, and 13. Four cases had mutations of the gene; three of these had deletions or loss of chromosome arm 7q., PTPN11 mutations are responsible for Noonan syndrome in Taiwanese patients, association of the PDGFRbeta with lipid raft microdomains renders it susceptible to LXA(4)-mediated dephosphorylation by possible reactivation of oxidatively inactivated SHP-2., understanding of Noonan syndrome and the LEOPARD syndrome pathogenesis will require solving the paradox that mutations oppositely influencing the biochemical activity of SHP-2 result in similar syndromes, Compund heterozygosity for Noonan syndrome-causing mutations in the PTPN11 gene, documenting association with early fetal death, is reported., The most prevalent links to PTPN11 gene dysfunction in cardiac development in patients with a PTPN11 mutation are pulmonary valve stenosis, atrial septal defect, ostium secundum type, and stenosis of the peripheral pulmonary arteries., Missense mutations were identified in 48.5% of the NS patients. There was a positive correlation between the presence of PTPN11 mutations and pulmonary stenosis frequency in NS patients., SHP-1 and SHP-2, two structurally related cytoplasmic protein-tyrosine phosphatases with different cellular functions and cell-specific expression patterns, were compared for their intrinsic susceptibility to oxidation by H(2)O(2)., Results describe the neurite outgrowth multiadaptor RhoGAP, NOMA-GAP, and show that it regulates neurite extension through SHP2 and Cdc42., occurrence of an unusual TG 3' splice site in intron 10, Virus attachment induced tyrosine phosphorylation of PVR; this permitted the association of PVR with SHP-2, a protein tyrosine phosphatase whose activation was required for entry and infection, FIRST CASE TO OUR KNOWLEDGE OF LS SYNDROME FEATURING A NEW PTPN11 GENE MUTATION, Frequently mutated in high hyperdiploid childhood acute lymphoblastic leukemia., Shp2E76K induces cytokine-independent survival of TF-1 cells by a novel mechanism involving up-regulation of Bcl-XL through the Erk1/2 pathway., SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation., correlation of PTPN11 mutations with NPM1 mutations and FLT3/ITD among adult AML patients, The finding that defective Shp2 signaling induced cell movement defects as early as gastrulation may have implications for the monitoring and diagnosis of Noonan and LEOPARD syndrome., There is little phenotype-genotype correlation with electrocardiographic findings in Noonan syndrome patients., analysis of the gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors, activation of SHP2 protein tyrosine phosphatase synergized with ICSBP haploinsufficiency to facilitate cytokine-induced myeloproliferation, apoptosis resistance, and rapid progression to AML in a murine bone marrow transplantation model., Mutations in the PTPN11 gene are commonly involved in the pathogenesis of Noonan syndrome but are not a common cause of idiopathic short stature., L282V substitution perturbs the stability of SHP2's closed conformation and T42A substitution promotes phosphopeptide-binding affinity., Shp2 binds most strongly when both of the NPXY motifs in LRP1 are phosphorylated, Our results demonstrate putative roles of SHP-1 and SHP-2 in the progression of both Condyloma acuminatum and cervical cancer after HPV infection., Shp2 mediates dephosphorylation of ROCKII and, therefore, regulates RhoA-induced cell rounding, indicating that Shp2 couples with RhoA signaling to control ROCKII activation during deadhesion., In 22 children with a mutation in PTPN11 mean gain in H-SDS for National standards was +1.3, not different from the mean gain in the five children without a mutation in PTPN11+1.3., the Gab1-SHP2-ERK1/2 signaling pathway comprises an inhibitory axis for IGF-I-dependent myogenic differentiation., Cdk2-associated complexes, by targeting SHP-1 for proteolysis, counteract the ability of SHP-1 to block cell cycle progression of intestinal epithelial cells, Mutations in PTPN11, which encodes the protein tyrosine phosphatase Shp2, are commonly found in juvenile myelomonocytic leukemia., SHP2 is a widely overexpressed signalling protein in infiltrating ductal carcinoma breast tumours., Data show that Shp2 activation promotes the dispersal of pre-patterned acetylcholine receptors (AChRs)clusters to facilitate the selective accumulation of AChRs at developing neuromuscular junction., Single nucleotide polymorphism at intron 3 of PTPN11 gene is associated with a lower risk of gastric atrophy., higher nuclear SHP2 expression in B-cell lymphoma cases, Hodgkin's lymphoma in a patient with Noonan syndrome with germ-line PTPN11 mutations., SHP-2 is a novel target of Abl kinases during cell proliferation, Shp-2 retains TERT in the nucleus by regulating tyrosine 707 phosphorylation., SHP2 activation induced by HCMV infection is responsible for the down-regulation of IFN-gamma-induced STAT1 tyrosine phosphorylation., Mutations in the PTPN11 are associated with Noonan syndrome., Juvenile myelomonocytic leukemia with PTPN11 mutation might be a distinct subgroup with specific clinical characteristics and poor outcome., Protein Tyrosine Phosphatase, Non-Receptor Type 11 modulates Cyclin-Dependent Kinase Inhibitor p27 stability and contributes to Cyclin-Dependent Kinase Inhibitor p27 -mediated cell cycle progression., Downregulation of platelet responsiveness upon contact with LDL by the protein-tyrosine phosphatases SHP-1 and SHP-2., Mutation analysis of PTPN11 was conducted on patient with severe form of Noonan Syndrome and Cafe-Au-Lait spots, using DNA sequencing. Results suggest additive effect of F285L mutation in PTPN11 may be associated Cafe-au-Lait spots., Results demonstrate that SHP-2 plays an important role in uPA-directed signaling and functional control of human VSMC and suggest that this phosphatase might contribute to the pathogenesis of the uPA-related vascular remodeling., genetic polymorphisms are biomarkers for ulcerative colitis susceptibility in the Japanese population, The kinetic and mechanistic details of reversible oxidation of SHP-1 and SHP-2, were investigated., In more than half the patients with Noonan Syndrome a mutation in the PTPN11 gene was identified., SHP2 promotes HER2-induced signaling and transformation at least in part by dephosphorylating a negative regulatory autophosphorylation site., These results suggest that SHP-2 regulates tyrosine phosphorylation of Cas-L, hence opposing the effect of kinases, and SHP-2 is a negative regulator of cell migration mediated by Cas-L., JAK2-SOCS1 and SHP2 reciprocally regulate ASK1 phosphorylation and stability in response to cytokines., results reveal a common signaling mechanism shared by human and mouse embryonic stem cells via Shp2 modulation of overlapping and divergent pathways, analysis of SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions, The activation of SHP-2 phosphorylation at Tyr542 in glioblastoma cell lines results in increased PTPase activity and distinct mechanisms of cell cycle progression and SHP-2. Its PTPase activity plays a critical role in EGFRvIII-mediated transformation., Independent NF1 and PTPN11 mutations in a family with neurofibromatosis-Noonan syndrome are reported., Stat3 is an essential signaling component potentially contributing to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia caused by PTPN11 gain-of-function mutations, Results suggest that increased c-Jun expression due to mutant Shp2-induced Ras hyperactivation, and reduced GATA2 expression promote aberrant monocytic differentiation induced by activating PTPN11 mutants., This study describes the association between the Gln510Glu mutation of the PTPN11 gene and lethal progressive hypertrophic cardiomyopathy (HCM) in a newborn with the NS phenotype., PTPN11 polymorphism is associated with a lower risk of severe gastric atrophy in Helicobacter pylori infections, but it is not associated with a decreased risk of gastric cancer in Japanese., SHP-2 is a component of the IGF signaling pathway that is required for normal placental growth., Investigated the prevalence of mutations in a relatively large cohort of primary embryonal Rhabdomyosarcoma (RMS) tumors. PTPN11 was found mutated in one tumor specimen, confirming that somatic defects in this gene are relatively uncommon in RMS., Data indicate that gastric cancers display a higher expression of PTPN11 protein than the normal cells, suggesting that neo-expression of this positive signaling protein in the cells might play a role in the cancer development., These data establish a novel role for SHP-2 phosphatase in the dopamine-mediated regulation of VEGFR-2 phosphorylation., This is the first report of mutations in both FBN1 and PTPN11 with combined phenotypes of Marfan and LEOPARD syndromes., Grb2 and FGFR2 interaction controls the activity of Shp2 toward FGFR2 which might suggest that signalling is influenced by factors other than simply growth factor engagement., two unrelated LEOPARD syndrome cases with a common PTPN11 mutation Y279C and with completely different clinical features, PTPN11 mutations in childhood acute lymphoblastic leukemia occur as a secondary event associated with high hyperdiploidy., Polymorphisms in NQO1, IL-10 and PTPN11, in combination with Helicobacter pylori status, could be used to identify individuals who are more likely to develop intestinal metaplasia and therefore gastric cancer., reports 4 cases of LEOPARD syndrome with point mutation of PTPN11 gene, assessment of PTPN11 mutations in juvenile myelomonocytic leukaemia, our studies have identified a new, KIR-independent role for SHP-2 in dampening NK cell activation in response to tumor target cells in a concentration-dependent manner, The authors find that activity of G protein coupled receptor protein of human herpesvirus 8 results in phosphorylation of regulatory tyrosines in Shp2 and that in turn, Shp2 is required for vGPCR-mediated activation of MEK, NFkappaB, and AP-1., Prenatal diagnosis of Noonan syndrome in a woman carrying a PTPN11 gene mutation., PRL diminished IGF-I-induced IGF-IR internalization, which may result from reduced SHP-2 association with IGF-IR, because we demonstrated an essential role for SHP-2 in IGF-IR internalization, Data show that the structure of SHP2 in complex with inhibitor II-B08 reveals molecular determinants that can be exploited for the acquisition of more potent and selective SHP2 inhibitors., Shp2 is specifically required for the initiation of retinal neurogenesis but not for the maintenance of the retinal differentiation program., PTPN11 mutations are associated with relapsed childhood high hyperdiploid acute lymphoblastic leukemia., Data show that PTPN11 mutations causing Leopard syndrome (LS) facilitate EGF-induced PI3K/AKT/GSK-3beta stimulation through impaired GAB1 dephosphorylation, resulting in deregulation of a novel signaling pathway that could be involved in LS pathology., These results suggest that calpain-dependent cleavage of SHP-1 and SHP-2 may contribute to protein tyrosine dephosphorylation in Jurkat T cell death induced by Entamoeba histolytica., IL-1-induced signaling through focal adhesions leading to MMP3 release and interactions between SHP-2 and PTPalpha are dependent on the integrity of the catalytic domains of PTPalpha., These findings highlight a novel negative regulatory role for integrin beta4 in endothelial cell inflammatory responses involving SHP-2-mediated MAPK signaling, identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype., Patients with Noonan syndrome and a PTPN11 mutation presented significantly higher prevalence of short stature (p = 0.03) and pulmonary valve stenosis (p = 0.01), and lower prevalence of hypertrophic cardiomyopathy (p = 0.01., Data suggest a model for the involvement of SHP-2 in PECAM-1-dependent motility in which SHP-2, recruited by its interaction with PECAM-1, targets paxillin to ultimately activate the MAPK pathway and downstream events required for cell motility., Tyr251 and Tyr301 of IL-22R1 are required for Shp2 binding and IL-22-induced Erk1/2 activation., The expression rate of SHP2 is high and closely correlated to lymphnode metastasis in NSCLC, which implies the occurrence and development of lung cancer maybe related to SHP2, and SHP2 maybe a new marker and therapeutic targets for lung cancer., Identification of the tumour-suppressive miRNA miR-489 and its target, PTPN11, might provide new insights into the underlying molecular mechanisms of hypopharyngeal squamous cell carcinoma, first report on molecular analysis and clinical features of a Turkish mother and son diagnosed with Noonan syndrome.The analysis revealed an A --> G transition at position 923 in exon 8 of the PTPN11 gene, indicating an Asn308Ser substitution., PECAM-1-mediated inhibition of GPVI-dependent platelet responses result from recruitment of SHP-2-p85 complexes to tyrosine-phosphorylated PECAM-1, which diminishes the association of PI3K with activatory signaling molecules Gab1 and LAT, Diagnosis of the syndrome was confirmed by the identification of earlier reported germline missense mutations in the PTPN11 gene., The enhancement of SHP2 expression in non-small cell lung cancer is correlated with tobacco smoking., Data describe how alpha6beta4 integrin selectively activates Fyn in response to receptor engagement, and show that both catalytic and noncatalytic functions of SHP2 are required for Fyn activation by alpha6beta4., The aim of this study was to evaluate phenotypic characteristics, PTPN11 gene mutations, and hematological and coagulation parameters in 30 clinically diagnosed cases of Noonan syndrome., it was possible to identify candidate genes that could be involved in the molecular mechanisms discriminating PTPN11 and RAS mutations in ALL, The authors show that vGPCR contains a bona fide immunoreceptor tyrosine-based inhibitory motif (ITIM) that binds and constitutively activates Shp2., These findings illustrate an essential role for SHP-2 in skeletal growth and remodeling., Germline PTPN11 mutation affecting exon 8 is associated with syndromic juvenile myelomonocytic leukemia., The role of protein tyrosine phosphatases in the regulation of steroid biosynthesis, relating them to steroidogenic acute regulatory protein, arachidonic acid metabolism and mitochondrial rearrangement, is described., SHP-2 as an essential component of tumor suppression and anoikis mediated by SIRPalpha1 in human breast carcinoma cells as well as in v-Src-transformed cells., Combination of computational and experimental methods are used to investigate the structural mechanism of opening of SHP2 and the impact of three gain-of-function mutants, D61G, E76K, and N308D, on the opening mechanism., study provides first evidence of an increased risk of cancer in patients with Noonan syndrome and a PTPN11 mutation, compared with that in the general population, The NS1 protein was observed to be expressed in 293T cells., Data suggest that SPARCL1, Shp2, MSH2, E-cadherin, p53, ADCY-2 and MAPK are potential prognostic markers in colorectal cancer., SPRED1 is a likely substrate of SHP2, whose tyrosine dephosphorylation is required to attenuate the inhibitory action of SPRED1 in the Ras/ERK pathway., Heterozygous loss-of-function mutations in PTPN11 are a frequent cause of metachondromatosis., The PTPN11 p.Gly409Ala mutation leads to a relatively mild Noonan syndrome-like phenotype., Decreased Shp2 expression was detected in a subfraction of human hepatocellular carcinoma specimens., Molecular analysis of PTPN11 gene of the total population revealed mutations in 17/80 Greek patients with Noonan syndrome. Pulmonary stenosis, short stature, and thorax deformities prevailed among those with PTPN11 mutations., For the first time it is shown that SHP-2 and PLCbeta1 are present as a preformed complex. Complex PLCbeta1 is tyr-phosphorylated basally. Ang II increased SHP-2-PLCbeta1 complexes and caused complex associated PLCbeta1 tyr-phosphorylation to decline., Results indicate an important role for SHP2 in STAT5 activation and GF-mediated proliferation, survival, and differentiation of CD34+ progenitor cells., PTPN11 gene was found most of the cases of Noonan syndrome., These results indicate that HLA-G is associated with activation of phosphatase SHP-2, which inhibits the mTOR pathway and favors the inhibition of the cell-cycle entry of human-activated T cells., the involvement of SHP2 activity in the regulation of the expression of the fatty acid-metabolizing enzyme ACSL4, regulation of the TLR3/TRIF-mediated pathway required the combined action of SHP-1 and SHP-2, which could be accomplished by CD300f but not CD300a., Data indicate that Shp2 is a tumor suppressor, and the decrease in Shp2 expression was a new prognostic marker in hepatocellular carcinoma (HCC)., high frequency of autoimmunity and alterations in the levels of Igs in patients harbouring mutations in PTPN11 was found which may suggest involvement of other PTPNs, besides PTPN22, in the regulation of the immunity, The E76 of exon 3 is the hot spot of PTPN11 mutation in childhood leukemia. The PTPN11 mutation does not associate with sex, age, WBC count, prednisone sensitivity test or early recurrence., a possible regulatory role of dimerization in SHP-2 function, Rare mutations in PTPN11 are known to cause the autosomal dominant condition Noonan syndrome, which includes congenital heart disease, by upregulating Ras/mitogen-activated protein kinase (MAPK) signaling., Further understanding of the physiologic and pathologic role of Shp2 in hematopoiesis and leukemogenesis, respectively, will yield information needed to develop therapeutic strategies targeted to Shp2 in human disease., In cervical cancers, SHP-2 mRNA and protein overexpression was associated with IFN-beta lower-expression., LST1 is expressed specifically in leukocytes of the myeloid lineage, where it localizes to the tetraspanin-enriched microdomains and it binds SHP-1 and SHP-2 phosphatases., SHP2 mediates chronic insulin-induced endothelial inflammation by limiting the production of NO in an endothelial NO synthase-independent and arginase-II-dependent manner., These results identify FGF-dependent maintenance of SHP2 as an important new mechanism controlling the extent of VE-cadherin tyrosine phosphorylation, thereby regulating its presence in adherens junctions and endothelial permeability., This report identifies two additional PTPs, SHP-2 and PTP-PEST, that are also directly activated by the Rb-E2F pathway and which can contribute to signal transduction during p53-independent apoptosis, Review, The modeling results indicate that SHP2 does not act as a feedback inhibitor in an early phase of IL-6-induced Jak/STAT signaling. However, experimental data reveal that SHP2 exhibits a basal repressory function., data demonstrate that the selection-by-function mechanism acting as driving force for PTPN11 mutations affecting codons 62 and 63 implies balancing of counteracting effects operating on the allosteric control of the function of SHP2, Changes in height SDS, height velocity, and serum IGF-1 level did not differ significantly between those children with or without PTPN11 mutations., Diminished functional role and altered localization of SHP2 in non-small cell lung cancer cells with EGFR-activating mutations., Congenital heart defects in the affected relatives were discordant in the families with PTPN11 mutations, and concordant in that with RAF1 mutation., This study provides the first evidence that rs12423190 polymorphism of the PTPN11 gene is significantly associated with an increased risk of gastric atrophy in the H. pylori-infected Chinese Han population., SHP2 phosphatase is essential for oncogenic KIT-induced growth and survival leading to myeloproliferative disease., PTPN11, which encodes tyrosine phosphatase Shp2, is a critical gene mediating cellular responses to hormones and cytokines. Recent experimental data suggest PTPN11/Shp2 acting as a tumor suppressor in hepatocarcinogenesis., SHP-2 phosphatase promotes cervical cancer cell proliferation through inhibiting IFN-beta production., findings show a previously unrecognized role for Shp2 in the maintenance of chromosome stability and suggest a new mechanism by which dysregulation of Shp2 signaling contributes to malignancy development, Selective inhibition or conditional knockout of Shp2 in lung epithelia reduces interleukin (IL)-8 release and pulmonary inflammation in cigarette smoke-exposed transgenic mice., A novel process is revealed in T cells in which phosphorylated transgene SHP-2 sequestrates STAT1 transcription factor in order to prevent signaling through the molecule., SHP2 phosphatase plays an important role in the recovery of disrupted endothelial cell-cell junctions by dephosphorylating VE-cadherin-associated beta-catenin and promoting the mobility of VE-cadherin at the plasma membrane., Overexpression of SHP2 and p38 enzymes in astrocytes led to elevated CXCL8 expression; however, inactivating SHP2 and p38 with dominant negative mutants abrogated CXCL8 induction, Shp2 is a component of the AKAP-Lbc complex and is inhibited by protein kinase A under pathological hypertrophic conditions in the heart., Human PROS inhibits VEGF-A-induced VEGFR2 activation at SHP2 sensitive sites., SHP2 phosphatase function regulates human hematopoietic cell development., SHP2 is both activated upon several DNA stress signals and is required for maintaining the checkpoint., Loss of cytoplasmic SHP-2 expression is associated with increased growth and prostatic cancer progression., Modulation of fatty acid synthase degradation by concerted action of p38 MAP kinase, E3 ligase COP1, and SH2-tyrosine phosphatase Shp2., Data suggest that the antitumor effects of Src inhibition in pancreatic cancer may be enhanced through simultaneous inhibition of SHP-2., tyrosine phosphorylation of Shp2 by EphA2 contributes to the phosphatase-independent Shp2-mediated activation of Extracellular Signal-Regulated MAP Kinases and might be involved in Shp2-associated diseases., SHP-2 is upregulated in gastric cancer and may be related to the development of gastric cancer. SHP-2 may be a potential prognostic marker of, or a therapeutic target for, gastric cancer., SHP-2 has a novel role in mediating human fibroblast-like synoviocytes function and suggest that it promotes the invasiveness and survival of these cells in rheumatoid arthritis., higher positive rates of expression in non-small cell lung cancer patients with lymph node metastases, These findings suggest for the first time an important role for SHP2 in APM-mediated escape of HNC cells from CTL recognition. Targeting SHP2 could enhance T-cell-based cancer immunotherapy., Report increased SHP-2 expression in helicobacter pylori-infected gastric neoplasms., results indicate that RSK directly phosphorylates Gab2 on 3 serine residues; findings show RSK-mediated Gab2 phosphorylation inhibits Shp2 recruitment, suggesting RSK mediates a negative-feedback loop that attenuates Gab2-dependent functions including cell motility, PGC rs6458238, PGC rs4711690 and PTPN11 rs12229892 were associated with susceptibilities to atrophic gastritis and/or gastric cancer., Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations., SHP2 promotes growth factor-induced cell movement by acting, at least in part, on FAK., SHP-2 mRNA levels were significantly reduced in intestinal biopsy specimens from ulcerative colitis patients., We found that H2 O2 induced SHP-2 activation, which acted as a suppressor in H2 O2 signalling to regulate MUC5AC transcription in the airway., Protein tyrosine phosphatase SHP2/PTPN11 mistargeting as a consequence of SH2-domain point mutations associated with Noonan Syndrome and leukemia., Blunted increase of IGF1 after the rGH generation test was present in children with Noonan syndrome due to mutations in the PTPN11 gene., SNPs of PTPN11 may play a role in serum lipids in a sex-specific pattern, Noonan syndrome mutations in the PTPN11 gene are not uniformly distributed as would be expected for a mutation hot spot but are highly clustered and showed an age-dependent germline mosaicism in testis., Oncogenic Shp2 disturbs microtubule regulation to cause HDAC6-dependent ERK hyperactivation., Cis-interactions between the C-terminal phosphotyrosines and SH2 domain within the protein tyrosine phosphatase Shp2 can be tuned by an adaptor protein, Grb2., Recurrent PTPN11 mutation causes noonan syndrome with multiple lentigines and medulloblastoma., SHP-2 is a key signalling node downstream of the DDR2 receptor in lung cancer., Studie provide evidence that SHP2 is a "druggable" target for the treatment of PTPN11-associated diseases and the compound #220-324 represents an ideal lead for the development of novel anti-SHP2 drugs., These data demonstrate that phosphorylated forms of LRP1 and PDGFRbeta compete for SHP-2 binding, and that expression of LRP1 attenuates SHP-2-mediated PDGF signaling events., The hnRNP Q is a novel substrate of SHP2 and the SHP2 activity may be also involved in RNA metabolisms via dephosphorylation of hnRNP Q., monobodies targeting the N-SH2 domain disrupted the interaction of SHP2 with its upstream activator, the Grb2-associated binder 2 adaptor protein, suggesting decoupling of SHP2 from the BCR-ABL protein complex, PTPN11 germline mutation may contribute to the development of scalp melanoma in Leopard syndrome., PTPN11 mutations had no impact on overall survival of patients with pediatric B cell precursor acute lymphoblastic leukemia., Loss of SHP-2 activity in CD4+ T cells promotes melanoma progression and metastasis., The SHP-2 is targeted by ROS produced in collagen-stimulated platelets and suggests that a novel mechanism for the regulation of platelet activation by ROS is due to oxidative inactivation of SHP-2., The expression of SHP-2 was significantly correlated with lymph node metastasis, but not with clinical stage and gender of patients with laryngeal carcinoma., screened 18 Chilean patients with a clinical diagnosis of NS for mutations in PTPN11 by high resolution melting (HRM) and subsequent sequencing, Knowing that NS is phenotypically heterogeneous, molecular characterization of the PTPN11 gene should serve to establish NS diagnosis in patients with atypical features, A single, novel mutation in the PTPN11 was identified in the proband with Noonan syndrome /multiple giant cell lesions; it occurred de novo in her mother with Noonan syndrome only, the activity of SHP-2, PTP-1beta, and PTP-PEST was enhanced by LKB1-expressing cells., Increased SHP2 expression is associated with laryngeal cancer., In the present series of patients from one family, all patients carry the same recurrent mutation Y279C in the PTPN11 gene, exhibiting different phenotypes and a variable expression of multiple lentigines., Deletion of the gene for Shp2 in transgenic mice blocks transformation of radial glia into Bergmann glia in cerebellum., In humans samples low SHP-2 expression showed a correlation with poor tumor differentiation and lymph node metastasis., SHP2E76K mutant promotes lung tumorigenesis., Myeloid progenitors with PTPN11 and nonRAS pathway gene mutations are refractory to treatment with 6-mercaptopurine in juvenile myelomonocytic leukemia, Appropriate Shp2 activity levels control the number as well as the differentiation of oligodendrocytes during development., X-ray structures of five NS/LS SHP2 mutants were ported and show how these mutations affect the interaction between different SHP2 domains. and its catalytic activity., A meta-analysis provided evidence that the PTPN11 G/A polymorphism appears to be protective against gastric atrophy in East Asians., PTP-1B, SHP-2, and PTEN all play a functional role in Rb/E2F-associated apoptotic signal transduction, A missense mutation of Tyr279Cys in the PTPN11 gene was determined in a sporadic case of Chinese Han., Data suggest an important role of SHP2 in the molecular etiology of breast tumor growth., a hypoxic environment may modulate JAK2-positive MPN cell fate and disease progression through the suppression of SHP-2 function and the subsequent suppression of JAK2V617F activity., these data indicate that in patients with MC, who are heterozygous for inherited PTPN11 loss-of-function mutations, second-hit mutations in PTPN11 can induce enchondromas by disrupting the organization and delaying the terminal differentiation, SHP2 is a crucial factor during early steps of TNBC migration to distant organs., Upregulation of SHP2 expression correlates with the migratory and invasive ability of oral cancer cells., Leopard syndrome-causing mutations not only affect SHP2 phosphatase activity but also induce a weakening of the intramolecular interaction between the N-SH2 and PTP domains, leading to mutants that are more readily activated by competing pTyr ligands., SHP2 drive ERK1/2 activity and antagonize STAT3 pathway., SHP2 silencing in mastocytoma cell line harboring KITD814Y mutation results in impaired signaling to ERK, Btk, Lyn and STAT5 pathways, and reduced rates of cell growth and colony formation., meta-analyses showed that the rs12526453 of PHACTR11 gene (OR = 1.14, p < 0.0001, random-effect method) and the rs11066301 of PTPN11 gene (OR = 1.15, p < 0.0001, fixed-effects method) were associated with CAD risk in multiple populations., High PTPN11 expression is associated with germinal center-derived lymphoma., findings suggested that the STR polymorphism within PTPN11 contributes to hepatocarcinogenesis, possibly by affecting PTPN11 expression through a structure-dependent mechanism, This finding not only provides an alternative mechanism for how CagA and ROS coregulate SHP2 activation but may also explain their roles in H. pylori-induced IFN-gamma resistance., While most of the work on SHP2 has focused on its role in the regulation of the MAPK/ERK signaling cascade, recent studies have emphasized the importance of other mechanisms and pathways that may be involved in essential SHP2 functions, particularly regarding heart development and disease. Many targets of SHP2 phosphatase activity have not been uncovered as yet. [Review], SHP2 positively regulates TGFbeta1-induced epithelial-mesenchymal transition modulated by its novel interacting protein Hook1., analysis of PTPN11 mutations in myelodysplastic syndrome in Korean patients, PD-1/SHP-2 has a role in inhibiting Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment, suggests that N-SH2 domain of SHP-2 is responsible for the binding of caveolin-1 and contributes to the regulation of Src phosphorylation and activation following ROS-induced oxidative stress in brain astrocytes, Results show that inhibition of the Shp2 PTP activity impairs mutant EGFR signaling and suppresses EGFRL858R-driven lung adenocarcinoma., mutations in particular regions of the PTPN11 gene show typical disease causing effects, the mutations in other parts of the coding regions may cause milder or unusual disease phenotype., SUMOylation of Shp2 promotes ERK activation via facilitating the formation of Shp2-Gab1 complex and accelerates hepatocellular carcinoma(HCC) cell and tumor growth, which presents a novel mechanism underlying Shp2 in regulation of HCC development., patients with low Shp2 expression exhibited superior prognosis to sorafenib, Our data show that inhibition of SHP2 induces BLT, ERalpha expression, dependency on estrogen for growth, and sensitivity to anti-hormone therapy., In vitro assays suggested that LEOPARD syndrome-associated SHP-2 mutations might enhance melanin synthesis in melanocytes, and that the activation of Akt/mTOR signalling may contribute to this process., EGFR-activated Src family kinases maintain GAB1-SHP2 complexes distal from EGFR., Silencing of SHP2 inhibited cell proliferation, invasion and vasculogenic mimicry in the glioma cell lines., Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition, Mutations clustered in exons 3 and 8 of the PTPN11 gene in a Moroccan Noonan syndrome cohort was screened for the first time., Shp-2 contributes to the control of respiratory syncytial virus replication and progeny production in pulmonary alveolar epithelial cells by interfering with IFN-alpha-induced Jak/Stat1 pathway activation, Data show that SNP interactions among H. pylori-related genes PGC, PTPN11, and IL1B, are associated with susceptibility to gastric carcinogenesis., PTPN11 Mutation is associated with Juvenile Myelomonocytic Leukemia., SHP2 may promote invadopodia formation through inhibition of Rho signaling in cancer cells., protein tyrosine phosphatase non-receptor type 1 and type 2 are potential therapeutic targets for breast cancer stem cells and gamma-T3 is a promising natural drug for future breast cancer therapy., PTPN11 is a central node in intrinsic and acquired resistance to targeted cancer drugs., a decrease in PTEN facilitates ROS/SHP2 signaling, causing lung cancer cells to become unresponsive to IFN-gamma, SHP-2 co-localized with the Cryptosporidium parvum sporozoite and this interaction increased the rate of C. parvum infectivity through SH2-mediated SHP-2 activity in intestinal epithelial cells., SHP2 preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signaling., The existence of a tight association between SHP2 and EGFR expression in tumors and cell lines further suggested the importance of SHP2 in EGFR expression., We found that LS-associated SHP2 mutants (Y279C, T468M, Q506P, and Q510E) exhibited a substantially reduced phosphatase activity toward parafibromin when compared with wild-type SHP2., find that Shp2 is distributed to the kinetochore, centrosome, spindle midzone, and midbody, Combined X-ray crystallography, small-angle X-ray scattering, and biochemistry to elucidate structural and mechanistic features of three cancer-associated SHP2 variants with single point mutations within the N-SH2,
OMIM_DISEASE LEOPARD syndrome 1, Metachondromatosis, Noonan syndrome 1, Leukemia, juvenile myelomonocytic, somatic,
SP_COMMENT catalytic activity:Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate., disease:Defects in PTPN11 are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:607785]. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. It is characterized by leukocytosis with tissue infiltration and in vitro hypersensitivity of myeloid progenitors to granulocyte-macrophage colony stimulating factor., disease:Defects in PTPN11 are a cause of Noonan-like syndrome [MIM:163955]; also known as Noonan-like/multiple giant cell lesion syndrome. It is an autosomal dominant disorder characterized by Noonan features associates with giant cell lesions of bone and soft tissue., disease:Defects in PTPN11 are the cause of LEOPARD syndrome [MIM:151100]. It is an autosomal dominant disorder allelic with Noonan syndrome. The acronym LEOPARD stands for lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness., disease:Defects in PTPN11 are the cause of Noonan syndrome 1 (NS1) [MIM:163950]. Noonan syndrome (NS) is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Mutations in PTPN11 account for more than 50% of the cases. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS1 inheritance is autosomal dominant., domain:The SH2 domains repress phosphatase activity. Binding of these domains to phosphotyrosine-containing proteins relieves this auto-inhibition, possibly by inducing a conformational change in the enzyme., function:Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus., PTM:Phosphorylated on Tyr-546 and Tyr-584 upon receptor protein tyrosine kinase activation; which creates a binding site for GRB2 and other SH2-containing proteins., similarity:Belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily., similarity:Contains 1 tyrosine-protein phosphatase domain., similarity:Contains 2 SH2 domains., subunit:Interacts with phosphorylated LIME1 and BCAR3. Interacts with SHB and INPP5D/SHIP1 (By similarity). Interacts with PTPNS1 and CD84. Interacts with phosphorylated SIT1 and MPZL1. Interacts with FCRL3, FCRL4, FCRL6 and ANKHD1., tissue specificity:Widely expressed, with highest levels in heart, brain, and skeletal muscle.,