Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature
- 27 February 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (11), 4257-4262
- https://doi.org/10.1073/pnas.1119803109
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.Keywords
This publication has 36 references indexed in Scilit:
- Noonan syndrome and clinically related disordersBest Practice & Research Clinical Endocrinology & Metabolism, 2011
- Altered Glucose Homeostasis in Mice with Liver-specific Deletion of Src Homology Phosphatase 2Published by Elsevier BV ,2010
- Functional Effects of PTPN11 (SHP2) Mutations Causing LEOPARD Syndrome on Epidermal Growth Factor-Induced Phosphoinositide 3-Kinase/AKT/Glycogen Synthase Kinase 3β SignalingMolecular and Cellular Biology, 2010
- PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in miceJCI Insight, 2010
- Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformationsProceedings of the National Academy of Sciences of the United States of America, 2009
- The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulationCurrent Opinion in Genetics & Development, 2009
- Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformationProceedings of the National Academy of Sciences of the United States of America, 2009
- Role of ERK1/2 signaling in congenital valve malformations in Noonan syndromeProceedings of the National Academy of Sciences of the United States of America, 2008
- Deletion of Ptpn11 (Shp2) in Cardiomyocytes Causes Dilated Cardiomyopathy via Effects on the Extracellular Signal–Regulated Kinase/Mitogen-Activated Protein Kinase and RhoA Signaling PathwaysCirculation, 2008
- Conditional Deletion of Shp2 in the Mammary Gland Leads to Impaired Lobulo-alveolar Outgrowth and Attenuated Stat5 ActivationPublished by Elsevier BV ,2006