title: 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 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1048  and Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires, F-31432 Toulouse,  France.
authors.forename: Audrey
authors.initials: A
authors.lastname: De Rocca Serra-Nédélec
authors.forename: Thomas
authors.initials: T
authors.lastname: Edouard
authors.forename: Karine
authors.initials: K
authors.lastname: Tréguer
authors.forename: Mylène
authors.initials: M
authors.lastname: Tajan
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Araki
authors.forename: Marie
authors.initials: M
authors.lastname: Dance
authors.forename: Marianne
authors.initials: M
authors.lastname: Mus
authors.forename: Alexandra
authors.initials: A
authors.lastname: Montagner
authors.forename: Maïté
authors.initials: M
authors.lastname: Tauber
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Salles
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.forename: Patrick
authors.initials: P
authors.lastname: Raynal
authors.forename: Armelle
authors.initials: A
authors.lastname: Yart
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D001699:Biometry; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D013006:Growth Hormone / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009634:Noonan Syndrome / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D050799:STAT5 Transcription Factor / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D048049:Extracellular Signal-Regulated MAP Kinases; D013006:Growth Hormone; D007334:Insulin-Like Growth Factor I; D053614:Janus Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D051057:Proto-Oncogene Proteins c-akt; D050799:STAT5 Transcription Factor; D018631:ras Proteins; C490897:Gab1 protein, mouse; C507926:Jak2 protein, mouse; C516725:Ptpn11 protein, mouse