scholarly journals PTPN11 (Protein Tyrosine Phosphatase, Nonreceptor Type 11) Mutations and Response to Growth Hormone Therapy in Children with Noonan Syndrome

2005 ◽  
Vol 90 (9) ◽  
pp. 5156-5160 ◽  
Author(s):  
Lize V. Ferreira ◽  
Silvia A. L. Souza ◽  
Ivo J. P. Arnhold ◽  
Berenice B. Mendonca ◽  
Alexander A. L. Jorge
Keyword(s):  
Outcome Measures ◽  
Protein Tyrosine Phosphatase ◽  
Noonan Syndrome ◽  
Tyrosine Phosphatase ◽  
University Hospital ◽  
Ptpn11 Gene ◽  
Protein Tyrosine ◽  
Igf I ◽  
Src Homology

Abstract Context: The cause of growth impairment in Noonan syndrome (NS) remains unclear. Mutations in PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) that codify constitutively activated Src homology protein tyrosine phosphatase-2 tyrosine phosphatase and may interfere with GH and IGF-I signaling were identified in approximately 40% of patients with NS. Objective: The objective of this study was to evaluate the influence of PTPN11 status on response to human GH (hGH) treatment in NS children with short stature. Setting: This study was performed at a university hospital. Design: The study design was to conduct a retrospective analysis of 3 yr of hGH treatment and genotyping of PTPN11 in patients with NS. Patients: Fourteen NS patients, half of them with PTPN11 mutations in heterozygous state, were studied. At the beginning of treatment, there were no clinical or laboratory differences between groups with and without mutations in the PTPN11 gene. Intervention: Patients were treated with hGH (47 μg/kg·d). Main Outcome Measures: The main outcome measures were PTPN11 genotype, change in IGF-I levels, and change in height sd score. Results: Patients with mutations in PTPN11 presented a significantly smaller increment in IGF-I levels during the treatment compared with patients without mutations (86 ± 67 and 202 ± 93 μg/liter, respectively; P = 0.03). hGH treatment significantly improved growth velocity in both groups, with slightly better results observed in patients without mutations. This was translated into greater gains in height sd score relation to baseline during the 3 yr of treatment in patients without mutations (+1.7 ± 0.1) compared with those with mutations (+0.8 ± 0.4; P < 0.01). Conclusions: Our findings suggest that the presence of PTPN11 mutations in patients with NS indicates a reduced growth response to long-term hGH treatment.

scholarly journals The Noonan syndrome-associated D61G variant of the protein tyrosine phosphatase SHP2 prevents synaptic down-scaling

2020 ◽  
Vol 295 (29) ◽  
pp. 10023-10031
Author(s):  
Wen Lu ◽  
Heng Ai ◽  
Fusheng Xue ◽  
Yifei Luan ◽  
Bin Zhang
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Noonan Syndrome ◽  
Hippocampal Neurons ◽  
Imaging Techniques ◽  
Tyrosine Phosphatase ◽  
Proper Function ◽  
Protein Tyrosine ◽  
Biochemical Assays ◽  
Src Homology ◽  
Src Homology 2 Domain

Homeostatic scaling of the synapse, such as synaptic down-scaling, has been proposed to offset deleterious effects induced by sustained synaptic strength enhancement. Proper function and subcellular distribution of Src homology 2 domain-containing nonreceptor protein tyrosine phosphatase (SHP2) are required for synaptic plasticity. However, the role of SHP2 in synaptic down-scaling remains largely unknown. Here, using biochemical assays and cell-imaging techniques, we found that synaptic SHP2 levels are temporally regulated during synaptic down-scaling in cultured hippocampal neurons. Furthermore, we observed that a Noonan syndrome-associated mutation of SHP2, resulting in a D61G substitution, prevents synaptic down-scaling. We further show that this effect is due to an inability of the SHP2-D61G variant to properly disassociate from postsynaptic density protein 95, leading to impaired SHP2 dispersion from synaptic sites after synaptic down-scaling. Our findings reveal a molecular mechanism of the Noonan syndrome-associated genetic variant SHP2-D61G that contributes to deficient synaptic down-scaling.

scholarly journals Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, non-receptor-type 11

2008 ◽  
Vol 159 (3) ◽  
pp. 203-208 ◽  
Author(s):  
C Noordam ◽  
P G M Peer ◽  
I Francois ◽  
J De Schepper ◽  
I van den Burgt ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Noonan Syndrome ◽  
Adult Height ◽  
Final Height ◽  
Tyrosine Phosphatase ◽  
Receptor Type ◽  
Gh Therapy ◽  
Gh Treatment ◽  
Protein Tyrosine

ContextNoonan syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. Short-term effect of GH therapy in NS is beneficial, reports on the effect on adult height are scarce.ObjectiveTo determine the effect of long-term GH therapy in children with NS.DesignTwenty-nine children with NS were treated with GH until final height was reached.SettingHospital endocrinology departments.PatientsChildren with the clinical diagnosis of NS, with mean age at the start of therapy of 11.0 years, 22 out of 27 tested children had a mutation in the protein tyrosine phosphatase, non-receptor-type 11 gene (PTPN11 gene).InterventionsGH was administered subcutaneously at 0.05 mg/kg per day until growth velocity was 1 cm/6 months.Main outcome measureLinear growth (height) was measured at 3-month intervals in the first year and at 6-month intervals thereafter until final height.ResultsAt the start of treatment, median height SDS (H-SDS) was −2.8 (−4.1 to −1.8) and 0.0 (−1.4 to +1.2), based on national and Noonan standards respectively. GH therapy lasted for 3.0–10.3 years (median, 6.4), producing mean gains in H-SDS of +1.3 (+0.2 to +2.7) and +1.3 (−0.6 to +2.4), based on national and Noonan standards respectively. 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 (P=0.98).ConclusionLong-term GH treatment in NS leads to attainment of adult height within the normal range in most patients.

Recent advances in the discovery of protein tyrosine phosphatase SHP2 inhibitors

2022 ◽  
Author(s):  
Jiao Kong ◽  
Yaqiu Long
Keyword(s):  
Cell Growth ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Ptpn11 Gene ◽  
Protein Tyrosine ◽  
Src Homology 2 ◽  
Receptor Protein Tyrosine Phosphatase ◽  
Src Homology ◽  
Src Homology 2 Domain

Src homology 2 domain-containing protein tyrosine phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the Ptpn11 gene, which regulates cell growth, differentiation and apoptosis via modulating various signaling...

Protein tyrosine phosphatase-α complexes with the IGF-I receptor and undergoes IGF-I-stimulated tyrosine phosphorylation that mediates cell migration

2009 ◽  
Vol 297 (1) ◽  
pp. C133-C139 ◽  
Author(s):  
Shirley C. Chen ◽  
Ranvikram S. Khanna ◽  
Darrell C. Bessette ◽  
Lionel A. Samayawardhena ◽  
Catherine J. Pallen
Keyword(s):  
Cell Migration ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Phosphorylation Site ◽  
Protein Tyrosine ◽  
Fibroblast Migration ◽  
Igf I ◽  
In Cells

Protein tyrosine phosphatase-α (PTPα) is a widely expressed receptor-type phosphatase that functions in multiple signaling systems. The actions of PTPα can be regulated by its phosphorylation on serine and tyrosine residues, although little is known about the conditions that promote PTPα phosphorylation. In this study, we tested the ability of several extracellular factors to stimulate PTPα tyrosine phosphorylation. The growth factors IGF-I and acidic FGF induced the highest increase in PTPα phosphorylation at tyrosine 789, followed by PMA and lysophosphatidic acid, while EGF had little effect. Further investigation of IGF-I-induced PTPα tyrosine phosphorylation demonstrated that this occurs through a novel Src family kinase-independent mechanism that does not require focal adhesion kinase, phosphatidylinositol 3-kinase, or MEK. We also show that PTPα physically interacts with the IGF-I receptor. In contrast to IGF-I-induced PTPα phosphorylation, this association does not require IGF-I. The interaction of PTPα and the IGF-I receptor is independent of PTPα catalytic activity, and expression of exogenous PTPα does not promote IGF-I receptor tyrosine dephosphorylation, indicating that PTPα does not act as an IGF-I receptor phosphatase. However, PTPα mediates IGF-I signaling, because IGF-I-stimulated fibroblast migration was reduced by ∼50% in cells lacking PTPα or in cells with mutant PTPα lacking the tyrosine 789 phosphorylation site. Our results suggest that PTPα tyrosine phosphorylation can occur in response to diverse stimuli and can be mediated by various tyrosine kinases. In the case of IGF-I, we propose that IGF-I-induced tyrosine 789 phosphorylation of PTPα, possibly catalyzed by the PTPα-associated IGF-I receptor tyrosine kinase, is required for efficient cell migration in response to this growth factor.

Molecular cloning of a novel protein-tyrosine phosphatase SH-PTP3 with sequence similarity to the src -homology region 2

FEBS Letters ◽  
1992 ◽  
Vol 314 (3) ◽  
pp. 335-339 ◽  
Author(s):  
Masaaki Adachi ◽  
Masuo Sekiya ◽  
Toshiki Miyachi ◽  
Keiki Matsuno ◽  
Yuji Hinoda ◽  
...  
Keyword(s):  
Molecular Cloning ◽  
Protein Tyrosine Phosphatase ◽  
Sequence Similarity ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine ◽  
Homology Region ◽  
Src Homology ◽  
Novel Protein
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