Functional Effects of PTPN11 (SHP2) Mutations Causing LEOPARD Syndrome on Epidermal Growth Factor-Induced Phosphoinositide 3-Kinase/AKT/Glycogen Synthase Kinase 3β Signaling

Autor: Serra-Nedelec, A., Treguer, K., Tajan, M., Araki, T., Dance, M., Mus, M., Montagner, A., Valet, P., Neel, B., Edouard, Thomas, Combier, Jean-Philippe, Nédélec, Audrey, Bel-Vialar, Sophie, Métrich, Mélanie, Conte-Auriol, Francoise, Lyonnet, Stanislas, Parfait, Béatrice, Tauber, Maithé, Salles, Jean-Pierre, Lezoualc'H, Frank, Yart, Armelle, Raynal, Patrick
Přispěvatelé: Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J)
Rok vydání: 2010
Předmět:
[SDV]Life Sciences [q-bio]
Recombinant Fusion Proteins
Protein Tyrosine Phosphatase
Non-Receptor Type 11
Chick Embryo
Protein tyrosine phosphatase
Biology
Glycogen Synthase Kinase 3
Phosphatidylinositol 3-Kinases
03 medical and health sciences
0302 clinical medicine
GSK-3
Epidermal growth factor
LEOPARD Syndrome
Animals
Humans
Myocytes
Cardiac
Phosphorylation
RNA
Small Interfering
Molecular Biology
Protein kinase B
GSK3B
ComputingMilieux_MISCELLANEOUS
Cells
Cultured
PI3K/AKT/mTOR pathway
Adaptor Proteins
Signal Transducing
030304 developmental biology
0303 health sciences
Glycogen Synthase Kinase 3 beta
Epidermal Growth Factor
Articles
Cell Biology
Fibroblasts
Molecular biology
Rats
3. Good health
Enzyme Activation
Mutation
Signal transduction
Proto-Oncogene Proteins c-akt
Atrial Natriuretic Factor
030217 neurology & neurosurgery
Signal Transduction
Zdroj: Molecular and Cellular Biology
Molecular and Cellular Biology, American Society for Microbiology, 2010, 30 (10), pp.2498-2507. ⟨10.1128/MCB.00646-09⟩
ISSN: 1098-5549
0270-7306
Popis: LEOPARD syndrome (LS), a disorder with multiple developmental abnormalities, is mainly due to mutations that impair the activity of the tyrosine phosphatase SHP2 (PTPN11). How these alterations cause the disease remains unknown. We report here that fibroblasts isolated from LS patients displayed stronger epidermal growth factor (EGF)-induced phosphorylation of both AKT and glycogen synthase kinase 3beta (GSK-3beta) than fibroblasts from control patients. Similar results were obtained in HEK293 cells expressing LS mutants of SHP2. We found that the GAB1/phosphoinositide 3-kinase (PI3K) complex was more abundant in fibroblasts from LS than control subjects and that both AKT and GSK-3beta hyperphosphorylation were prevented by reducing GAB1 expression or by overexpressing a GAB1 mutant unable to bind to PI3K. Consistently, purified recombinant LS mutants failed to dephosphorylate GAB1 PI3K-binding sites. These mutants induced PI3K-dependent increase in cell size in a model of chicken embryo cardiac explants and in transcriptional activity of the atrial natriuretic factor (ANF) gene in neonate rat cardiomyocytes. In conclusion, SHP2 mutations causing LS facilitate EGF-induced PI3K/AKT/GSK-3beta stimulation through impaired GAB1 dephosphorylation, resulting in deregulation of a novel signaling pathway that could be involved in LS pathology.
Databáze: OpenAIRE
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