ArticleJCI insight2020
Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines.
Article in JCI insight, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 19 citations in OpenAlex.
- A novel therapeutic monoclonal antibody targeting PZR demonstrates potent anti-metastatic efficacy in triple-negative breast cancer.Journal of translational medicine · 2026Article
- Multiplexed single-cell transcriptomics reveals diverse phenotypic outcomes for pathogenic SHP2 variants.Science advances · 2026Article
- Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants.EMBO reports · 2026Article
- A novel anti-CD20, concabody, enhances immunotherapy efficacy by targeting MPZL1 and augmenting antibody-induced cell death.Frontiers in oncology · 2026Article
- Progastrin Promotes Colorectal Cancer Stem Cell-Like Properties via the Receptor PZR.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants.bioRxiv : the preprint server for biology · 2025Article
- SHP2 genetic variants in NSML-associated RASopathies disrupt the PZR-IRX transcription factor signaling axis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Machine learning and experimental validation of novel biomarkers for hypertrophic cardiomyopathy and cancers.Journal of cellular and molecular medicine · 2024Article
- Probing the Immunoreceptor Tyrosine-Based Inhibition Motif Interaction Protein Partners with Proteomics.Molecules (Basel, Switzerland) · 2024Article
- Mechanisms Underlying the Therapeutic Effects of Nicotinamide Mononucleotide in Treating High-fat Diet-induced Hypertrophic Cardiomyopathy based on GEO Datasets, Network Pharmacology, and Molecular Docking.Current pharmaceutical design · 2024Article
- MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention.Nature communications · 2023Article
- Article
- Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines.Cardiovascular drugs and therapy · 2022Article
- Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy.Signal transduction and targeted therapy · 2022Review
- Friend or foe? Unraveling the complex roles of protein tyrosine phosphatases in cardiac disease and development.Cellular signalling · 2022Review
- Modeling (not so) rare developmental disorders associated with mutations in the protein-tyrosine phosphatase SHP2.Frontiers in cell and developmental biology · 2022Review
- Integrated in silico MS-based phosphoproteomics and network enrichment analysis of RASopathy proteins.Orphanet journal of rare diseases · 2021Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Noonan syndrome with multiple lentigines (NSML) is a rare autosomal dominant disorder that presents with cardio-cutaneous-craniofacial defects. Hypertrophic cardiomyopathy (HCM) represents the major life-threatening presentation in NSML. Mutations in the PTPN11 gene that encodes for the protein tyrosine phosphatase (PTP), SHP2, represents the predominant cause of HCM in NSML. NSML-associated PTPN11 mutations render SHP2 catalytically inactive with an "open" conformation. NSML-associated PTPN11 mutations cause hypertyrosyl phosphorylation of the transmembrane glycoprotein, protein zero-related (PZR), resulting in increased SHP2 binding. Here we show that NSML mice harboring a tyrosyl phosphorylation-defective mutant of PZR (NSML/PZRY242F) that is defective for SHP2 binding fail to develop HCM. Enhanced AKT/S6 kinase signaling in heart lysates of NSML mice was reversed in NSML/PZRY242F mice, demonstrating that PZR/SHP2 interactions promote aberrant AKT/S6 kinase activity in NSML. Enhanced PZR tyrosyl phosphorylation in the hearts of NSML mice was found to drive myocardial fibrosis by engaging an Src/NF-κB pathway, resulting in increased activation of IL-6. Increased expression of IL-6 in the hearts of NSML mice was reversed in NSML/PZRY242F mice, and PZRY242F mutant fibroblasts were defective for IL-6 secretion and STAT3-mediated fibrogenesis. These results demonstrate that NSML-associated PTPN11 mutations that induce PZR hypertyrosyl phosphorylation trigger pathophysiological signaling that promotes HCM and cardiac fibrosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.