ArticleMolecular and cellular biology2010
Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling.
Article in Molecular and cellular biology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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47 citing papers in PubMed, 102 citations in OpenAlex.
- Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants.EMBO reports · 2026Article
- Interpreting the functional impact of genetic variants: The need for context qualifiers.American journal of human genetics · 2026Review
- 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
- Genotype-phenotype correlations with autism spectrum disorder-related traits in noonan syndrome and noonan syndrome with multiple lentigines: a cross-sectional study.Molecular autism · 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
- Discovery of TK-642 as a highly potent, selective, orally bioavailable pyrazolopyrazine-based allosteric SHP2 inhibitor.Acta pharmaceutica Sinica. B · 2024Article
- Novel therapeutic perspectives in Noonan syndrome and RASopathies.European journal of pediatrics · 2024Review
- Time-dependent effects of BRAF-V600E on cell cycling, metabolism, and function in engineered myocardium.Science advances · 2024Article
- Atomistic ensemble of active SHP2 phosphatase.Communications biology · 2023Article
- Deletion of PDKJournal of cardiovascular translational research · 2023Article
- An integrated genetic analysis of epileptogenic brain malformed lesions.Acta neuropathologica communications · 2023Article
- Skeletal defects and bone metabolism in Noonan, Costello and cardio-facio-cutaneous syndromes.Frontiers in endocrinology · 2023Review
- Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines.Cardiovascular drugs and therapy · 2022Article
- The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery.American journal of medical genetics. Part A · 2022Article
- Friend or foe? Unraveling the complex roles of protein tyrosine phosphatases in cardiac disease and development.Cellular signalling · 2022Review
- Recent advances in the discovery of protein tyrosine phosphatase SHP2 inhibitors.RSC medicinal chemistry · 2022Review
- Endocrine system involvement in patients with RASopathies: A case series.Frontiers in endocrinology · 2022Article
- Integrated in silico MS-based phosphoproteomics and network enrichment analysis of RASopathy proteins.Orphanet journal of rare diseases · 2021Article
- The loops of the N-SH2 binding cleft do not serve as allosteric switch in SHP2 activation.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
LEOPARD syndrome (LS), a disorder with multiple developmental abnormalities, is mainly due to mutations that impair the activity of the tyrosine phosphatase SHP2 (PTPN11). How these alterations cause the disease remains unknown. We report here that fibroblasts isolated from LS patients displayed stronger epidermal growth factor (EGF)-induced phosphorylation of both AKT and glycogen synthase kinase 3beta (GSK-3beta) than fibroblasts from control patients. Similar results were obtained in HEK293 cells expressing LS mutants of SHP2. We found that the GAB1/phosphoinositide 3-kinase (PI3K) complex was more abundant in fibroblasts from LS than control subjects and that both AKT and GSK-3beta hyperphosphorylation were prevented by reducing GAB1 expression or by overexpressing a GAB1 mutant unable to bind to PI3K. Consistently, purified recombinant LS mutants failed to dephosphorylate GAB1 PI3K-binding sites. These mutants induced PI3K-dependent increase in cell size in a model of chicken embryo cardiac explants and in transcriptional activity of the atrial natriuretic factor (ANF) gene in neonate rat cardiomyocytes. In conclusion, SHP2 mutations causing 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.
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