ArticleProceedings of the National Academy of Sciences of the United States of America2012
Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers, 1 of them a synthesis that pooled it.
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Who cites it
62 citing papers in PubMed, 1 synthesis or guideline pooled it, 117 citations in OpenAlex.
- Update on the Clinical and Molecular Characterization of Noonan Syndrome and Other RASopathies: A Retrospective Study and Systematic Review.International journal of molecular sciences · 2025Pooled it
- RAS/MAPK pathway modulation with simvastatin in children with Noonan syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.EClinicalMedicine · 2026Article
- Cadmium impairs heart ventricular formation and disrupts polysialylated-NCAM/FGF receptor signaling in Xenopus tadpoles.Cell & bioscience · 2026Article
- Pathogenesis of Noonan Syndrome is Modulated by NOC2L, a Novel Interactor of LZTR1 Leading to Impaired P53 Signalling.The Journal of clinical endocrinology and metabolism · 2026Article
- SHP2: A Redox-Sensitive Regulator Linking Immune Checkpoint Inhibitor Therapy to Cancer Treatment and Vascular Risk.Antioxidants (Basel, Switzerland) · 2025Review
- Noonan syndrome withTranslational pediatrics · 2025Article
- Evaluation of Growth Characteristics and Final Height of Cases Diagnosed with Noonan Syndrome on Growth Hormone TreatmentJournal of clinical research in pediatric endocrinology · 2025Article
- EndoCompass Project: Research Roadmap for Growth Disorders.Hormone research in paediatrics · 2025Review
- Spectrum of Mutations inGenes · 2024Article
- Novel therapeutic perspectives in Noonan syndrome and RASopathies.European journal of pediatrics · 2024Review
- Growth Hormone Treatment for Non-GHD Disorders: Excitement Tempered by Biology.The Journal of clinical endocrinology and metabolism · 2024Review
- Genetic backgrounds and genotype-phenotype relationships in anthropometric parameters of 116 Japanese individuals with Noonan syndrome.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2024Article
- Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease.Frontiers in molecular neuroscience · 2024Review
- Neuroimmune pathways involvement in neurodegeneration of R6/2 mouse model of Huntington's disease.Frontiers in cellular neuroscience · 2024Article
- Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.Nature communications · 2023Article
- The Cell-Specific Role of SHP2 in Regulating Bone Homeostasis and Regeneration Niches.International journal of molecular sciences · 2023Review
- Skeletal defects and bone metabolism in Noonan, Costello and cardio-facio-cutaneous syndromes.Frontiers in endocrinology · 2023Review
- The Tyrosine Phosphatase SHP2: A New Target for Insulin Resistance?Biomedicines · 2022Review
- Dissecting protein tyrosine phosphatase signaling by engineered chemogenetic control of its activity.The Journal of cell biology · 2022Article
- A pan-cancer analysis confirms PTPN11's potential as a prognostic and immunological biomarker.Aging · 2022Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 7 institutions in 2 countries.
Funding
Abstract
Noonan syndrome (NS), a genetic disease caused in half of cases by activating mutations of the tyrosine phosphatase SHP2 (PTPN11), is characterized by congenital cardiopathies, facial dysmorphic features, and short stature. How mutated SHP2 induces growth retardation remains poorly understood. We report here that early postnatal growth delay is associated with low levels of insulin-like growth factor 1 (IGF-1) in a mouse model of NS expressing the D61G mutant of SHP2. Conversely, inhibition of SHP2 expression in growth hormone (GH)-responsive cell lines results in increased IGF-1 release upon GH stimulation. SHP2-deficient cells display decreased ERK1/2 phosphorylation and rat sarcoma (RAS) activation in response to GH, whereas expression of NS-associated SHP2 mutants results in ERK1/2 hyperactivation in vitro and in vivo. RAS/ERK1/2 inhibition in SHP2-deficient cells correlates with impaired dephosphorylation of the adaptor Grb2-associated binder-1 (GAB1) on its RAS GTPase-activating protein (RASGAP) binding sites and is rescued by interfering with RASGAP recruitment or function. We demonstrate that inhibition of ERK1/2 activation results in an increase of IGF-1 levels in vitro and in vivo, which is associated with significant growth improvement in NS mice. In conclusion, NS-causing SHP2 mutants inhibit GH-induced IGF-1 release through RAS/ERK1/2 hyperactivation, a mechanism that could contribute to growth retardation. This finding suggests that, in addition to its previously shown beneficial effect on NS-linked cardiac and craniofacial defects, RAS/ERK1/2 modulation could also alleviate the short stature phenotype in NS caused by PTPN11 mutations.
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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.