2012
DOI: 10.1073/pnas.1119803109
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Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature

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 … Show more

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Cited by 107 publications
(78 citation statements)
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“…Interestingly, this study also showed that treating NS mice with a Mek inhibitor restores IGF-1 level and increases their growth [64]. In agreement with this, earlier reports incidentally showed that Mek inhibitors can rescue growth defect in other NS mouse models (RAF1 L613V/+ and SOS1 E846K/E846K ) [7,66].…”
Section: Role Of Ptpn11/shp2 Mutant Causing Ns In Ras/mapk Upregulatisupporting
confidence: 77%
See 3 more Smart Citations
“…Interestingly, this study also showed that treating NS mice with a Mek inhibitor restores IGF-1 level and increases their growth [64]. In agreement with this, earlier reports incidentally showed that Mek inhibitors can rescue growth defect in other NS mouse models (RAF1 L613V/+ and SOS1 E846K/E846K ) [7,66].…”
Section: Role Of Ptpn11/shp2 Mutant Causing Ns In Ras/mapk Upregulatisupporting
confidence: 77%
“…These mice exhibit a smaller size, which is associated with lower blood concentrations of IGF-1 and IGFBP-3 than in wild doi: 10.7243/2052-8000-2-1 type animals [64]. Therefore this mouse model appeared to present similar endocrine dysregulations as those observed in children with NS.…”
Section: Role Of Ptpn11/shp2 Mutant Causing Ns In Ras/mapk Upregulatimentioning
confidence: 61%
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“…Mutations in these genes can also cause short stature without obvious clinical features (158). Inhibition of IGF1 release via GH-induced ERK hyperactivation or EGF-induced PI3K/AKT/GSK-3b stimulation may contribute to short stature in patients with PTPN11 mutations (159,160). Genetic aberrations in several other intracellular pathways play a role in short stature syndromes.…”
Section: Genetic Defects Of Intracellular Pathwaysmentioning
confidence: 99%