A Substrate Trapping Mutant Form of Striatal-Enriched Protein Tyrosine Phosphatase Prevents Amphetamine-Induced Stereotypies and Long-Term Potentiation in the Striatum

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.

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Natural α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitors: A Source of Scaffold Molecules for Synthesis of New Multitarget Antidiabetic Drugs

Molecules ◽

10.3390/molecules26164818 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4818

Author(s):

Massimo Genovese ◽

Ilaria Nesi ◽

Anna Caselli ◽

Paolo Paoli

Keyword(s):

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Antidiabetic Drugs ◽

Protein Tyrosine Phosphatase 1B ◽

Protein Tyrosine ◽

Lead Compounds ◽

Limited Effectiveness ◽

Biological Target ◽

Dual Inhibitors

Diabetes mellitus (DM) represents a group of metabolic disorders that leads to acute and long-term serious complications and is considered a worldwide sanitary emergence. Type 2 diabetes (T2D) represents about 90% of all cases of diabetes, and even if several drugs are actually available for its treatment, in the long term, they show limited effectiveness. Most traditional drugs are designed to act on a specific biological target, but the complexity of the current pathologies has demonstrated that molecules hitting more than one target may be safer and more effective. The purpose of this review is to shed light on the natural compounds known as α-glucosidase and Protein Tyrosine Phosphatase 1B (PTP1B) dual-inhibitors that could be used as lead compounds to generate new multitarget antidiabetic drugs for treatment of T2D.

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Leukemia-Associated, Constitutively Active Mutants of SHP2 Protein Tyrosine Phosphatase Inhibit NF1 Transcriptional Activation by the Interferon Consensus Sequence Binding Protein

Molecular and Cellular Biology ◽

10.1128/mcb.00036-06 ◽

2006 ◽

Vol 26 (17) ◽

pp. 6311-6332 ◽

Cited By ~ 32

Author(s):

Weiqi Huang ◽

Gurveen Saberwal ◽

Elizabeth Horvath ◽

Chunliu Zhu ◽

Stephan Lindsey ◽

...

Keyword(s):

Negative Feedback ◽

Protein Tyrosine Phosphatase ◽

Binding Protein ◽

Tyrosine Phosphatase ◽

Consensus Sequence ◽

Myeloid Cells ◽

Feedback Mechanism ◽

Mutant Form ◽

Protein Tyrosine ◽

Negative Feedback Mechanism

ABSTRACT Deficiency in either the interferon consensus sequence binding protein (ICSBP) or neurofibromin 1 (Nf1) increases the proliferative response of myeloid progenitor cell to hematopoietic cytokines. Consistent with this, we previously demonstrated that ICSBP activates transcription of the gene encoding Nf1 (the NF1 gene). In the studies presented here, we determine that ICSBP tyrosine phosphorylation is necessary for the activation of NF1 transcription. Since ICSBP is tyrosine phosphorylated in response to hematopoietic cytokines, these studies identify a novel pathway by which cytokine-induced posttranslational modification of ICSBP results in NF1 transcription. Nf1 subsequently inactivates cytokine-activated Ras, thereby creating a negative feedback mechanism for cytokine-induced proliferation. In these studies, we also determine that ICSBP is a substrate for SHP2 protein tyrosine phosphatase (SHP2-PTP). We find that wild-type SHP2-PTP dephosphorylates ICSBP only in undifferentiated myeloid cells. In contrast, a leukemia-associated, constitutively activated mutant form of SHP2-PTP dephosphorylates ICSBP in both myeloid progenitors and differentiating myeloid cells. Activated SHP2-PTP mutants thereby inhibit ICSBP-dependent NF1 transcription, impairing this negative feedback mechanism on cytokine-activated Ras. Therefore, these studies suggest that leukemia-associated ICSBP deficiency cooperates with leukemia-associated activating mutants of SHP2-PTP to contribute to the proliferative phenotype in myeloid malignancies.

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-2559 ◽

2005 ◽

Vol 90 (9) ◽

pp. 5156-5160 ◽

Cited By ~ 44

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.

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