Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature
| Autor: | Mylène Tajan, Marianne Mus, Thomas Edouard, Karine Tréguer, Jean-Pierre Salles, Alexandra Montagner, Armelle Yart, Patrick Raynal, Toshiyuki Araki, M. Tauber, Philippe Valet, Audrey De Rocca Serra-Nédélec, Marie Dance, Benjamin G. Neel |
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| Přispěvatelé: | Tréguer, Karine, Tajana, Mylène, Yart, Armelle, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Endocrinologie, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Campbell Family Cancer Research Institute, University of Toronto-Ontario Cancer Institute, Laboratoire de biologie moléculaire eucaryote (LBME), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Mécanismes des cardiopathies et résistance hormonale dans le Noonan et syndrome apparentés (M2CHRNRS), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Ontario Cancer Institute, Melanie H. Cobb, Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), ProdInra, Archive Ouverte |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
MAPK/ERK pathway
TYROSINE-PHOSPHATASE SHP2 medicine.medical_treatment [SDV]Life Sciences [q-bio] MESH: Insulin-Like Growth Factor I Protein Tyrosine Phosphatase Non-Receptor Type 11 Protein tyrosine phosphatase growth hormone insensitivity MESH: Animals Newborn MESH: Janus Kinase 2 [SHS]Humanities and Social Sciences Mice Phosphatidylinositol 3-Kinases Insulin-like growth factor 0302 clinical medicine HEIGHT STAT5 Transcription Factor MESH: Animals Insulin-Like Growth Factor I Phosphorylation Extracellular Signal-Regulated MAP Kinases MESH: Biometry MESH: Extracellular Signal-Regulated MAP Kinases ComputingMilieux_MISCELLANEOUS 0303 health sciences Multidisciplinary Noonan Syndrome ACTIVATED PROTEIN-KINASE MOUSE MODEL DEFECTS Biological Sciences [SDV] Life Sciences [q-bio] MESH: Noonan Syndrome Signal transduction medicine.symptom signaling MESH: Protein Tyrosine Phosphatase Non-Receptor Type 11 MESH: ras Proteins medicine.medical_specialty MESH: Enzyme Activation Biometry MESH: Mutation MESH: Rats 030209 endocrinology & metabolism SIGNALING PATHWAYS PTPN11 SHP2 MUTATIONS DELETION MALFORMATIONS Biology Short stature MESH: Mitogen-Activated Protein Kinase Kinases MESH: Phosphoproteins 03 medical and health sciences Internal medicine medicine Animals MESH: Mice Adaptor Proteins Signal Transducing 030304 developmental biology Mitogen-Activated Protein Kinase Kinases Binding Sites MESH: Phosphorylation MESH: Proto-Oncogene Proteins c-akt Growth factor MESH: STAT5 Transcription Factor Janus Kinase 2 Phosphoproteins medicine.disease Rats Enzyme Activation PTPN11 Endocrinology Animals Newborn MESH: Binding Sites MESH: Phosphatidylinositol 3-Kinases Growth Hormone MESH: Growth Hormone Mutation ras Proteins Noonan syndrome Proto-Oncogene Proteins c-akt |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America 11 (109), 4257-4262. (2012) Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2012, 109 (11), pp.4257-62. ⟨10.1073/pnas.1119803109⟩ Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2012, 109 (11), pp.4257-4262. ⟨10.1073/pnas.1119803109⟩ Proceedings of the National Academy of Sciences of the United States of America, 2012, 109 (11), pp.4257-4262. ⟨10.1073/pnas.1119803109⟩ |
| ISSN: | 0027-8424 1091-6490 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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