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: Audrey De Rocca Serra-Nédélec, Thomas Edouard, Karine Tréguer, Mylène Tajan, Toshiyuki Araki, Marie Dance, Marianne Mus, Alexandra Montagner, Maïté Tauber, Jean-Pierre Salles, Philippe Valet, Benjamin G Neel, Patrick Raynal, Armelle Yart
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 11 Pg. 4257-62 (Mar 13 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22371576 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Gab1 protein, mouse
• Phosphoproteins
• STAT5 Transcription Factor
• Insulin-Like Growth Factor I
• Growth Hormone
• Jak2 protein, mouse
• Janus Kinase 2
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase Kinases
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Ptpn11 protein, mouse
• ras Proteins

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Animals, Newborn
• Binding Sites
• Biometry
• Enzyme Activation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Growth Hormone (pharmacology)
• Insulin-Like Growth Factor I (biosynthesis, metabolism)
• Janus Kinase 2 (metabolism)
• Mice
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Mutation (genetics)
• Noonan Syndrome (blood, enzymology, genetics)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoproteins (metabolism)
• Phosphorylation (drug effects)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• STAT5 Transcription Factor (metabolism)
• ras Proteins (metabolism)