ArticleHuman molecular genetics2008
Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes.
Article in Human molecular genetics, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 99 citations in OpenAlex.
- Biallelic loss-of-function PTPN6 variants lead to inflammatory lung disease and hemolytic anemia.The Journal of experimental medicine · 2026Article
- Multiplexed single-cell transcriptomics reveals diverse phenotypic outcomes for pathogenic SHP2 variants.Science advances · 2026Article
- Decoding C‑SH2 Domain/Peptide Interactions in SH2 Domain-Containing Tyrosine Phosphatase 2: A Molecular Framework for Rational Inhibitor Design.ACS omega · 2026Article
- Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants.EMBO reports · 2026Article
- Phosphatase SHP2 pathogenic mutations enhance activity by altering conformational sampling.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Hypertrophic Cardiomyopathy Genotype-Phenotype Analysis in Lithuanian Single-Center Cohort.International journal of molecular sciences · 2025Article
- Phosphatase SHP2 pathogenic mutations enhance activity by altering conformational sampling.bioRxiv : the preprint server for biology · 2025Article
- The pathogenic E139D mutation stabilizes a non-canonical active state of the multi-domain phosphatase SHP2.Protein science : a publication of the Protein Society · 2025Article
- The pathogenic E139D mutation stabilizes a non-canonical active state of the multi-domain phosphatase SHP2.bioRxiv : the preprint server for biology · 2025Article
- Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants.bioRxiv : the preprint server for biology · 2025Article
- Deep mutational scanning of the multi-domain phosphatase SHP2 reveals mechanisms of regulation and pathogenicity.Nature communications · 2025Article
- The pathogenic T42A mutation in SHP2 rewires the interaction specificity of its N-terminal regulatory domain.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The pathogenic T42A mutation in SHP2 rewires the interaction specificity of its N-terminal regulatory domain.bioRxiv : the preprint server for biology · 2024Article
- Mutations in PTPN11 could lead to a congenital myasthenic syndrome phenotype: a Noonan syndrome case series.Journal of neurology · 2024Article
- Atomistic ensemble of active SHP2 phosphatase.Communications biology · 2023Article
- Prenatal genetic diagnosis associated with fetal ventricular septal defect: an assessment based on chromosomal microarray analysis and exome sequencing.Frontiers in genetics · 2023Article
- Computational Evaluation of Peptide-Protein Binding Affinities: Application of Potential of Mean Force Calculations to SH2 Domains.Methods in molecular biology (Clifton, N.J.) · 2023Article
- SH2 Domains: Folding, Binding and Therapeutical Approaches.International journal of molecular sciences · 2022Review
- Article
- Recent advances in the discovery of protein tyrosine phosphatase SHP2 inhibitors.RSC medicinal chemistry · 2022Review
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
Missense PTPN11 mutations cause Noonan and LEOPARD syndromes (NS and LS), two developmental disorders with pleiomorphic phenotypes. PTPN11 encodes SHP2, an SH2 domain-containing protein tyrosine phosphatase functioning as a signal transducer. Generally, different substitutions of a particular amino acid residue are observed in these diseases, indicating that the crucial factor is the residue being replaced. For a few codons, only one substitution is observed, suggesting the possibility of specific roles for the residue introduced. We analyzed the biochemical behavior and ligand-binding properties of all possible substitutions arising from single-base changes affecting codons 42, 139, 279, 282 and 468 to investigate the mechanisms underlying the invariant occurrence of the T42A, E139D and I282V substitutions in NS and the Y279C and T468M changes in LS. Our data demonstrate that the isoleucine-to-valine change at codon 282 is the only substitution at that position perturbing the stability of SHP2's closed conformation without impairing catalysis, while the threonine-to-alanine change at codon 42, but not other substitutions of that residue, promotes increased phosphopeptide-binding affinity. The recognition specificity of the C-SH2 domain bearing the E139D substitution differed substantially from its wild-type counterpart acquiring binding properties similar to those observed for the N-SH2 domain, revealing a novel mechanism of SHP2's functional dysregulation. Finally, while functional selection does not seem to occur for the substitutions at codons 279 and 468, we point to deamination of the methylated cytosine at nucleotide 1403 as the driving factor leading to the high prevalence of the T468M change in LS.
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