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

被引:74
作者
Edouard, Thomas [1 ]
Combier, Jean-Philippe [1 ]
Nedelec, Audrey [1 ]
Bel-Vialar, Sophie [4 ]
Metrich, Melanie [5 ]
Conte-Auriol, Francoise [1 ,2 ,3 ]
Lyonnet, Stanislas [6 ,7 ]
Parfait, Beatrice [8 ,9 ]
Tauber, Maithe [1 ,2 ,3 ]
Salles, Jean-Pierre [1 ,2 ,3 ]
Lezoualc'h, Frank [5 ]
Yart, Armelle [1 ]
Raynal, Patrick [1 ,2 ,3 ]
机构
[1] Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France
[2] CHRU, F-31059 Toulouse, France
[3] Univ Toulouse 3, Hop Purpan, F-31059 Toulouse, France
[4] CNRS, UMR5547, Ctr Dev Biol, F-31062 Toulouse, France
[5] Univ Paris 11, INSERM, UMRS Signalisat & Physiopathol Cardiaque 769, F-92296 Chatenay Malabry, France
[6] Univ Paris 05, F-75743 Paris, France
[7] Hop Necker Enfants Malad, INSERM, U781, F-75743 Paris, France
[8] Univ Paris 05, F-75270 Paris, France
[9] UFR Pharmacie, INSERM, U745, F-75270 Paris, France
关键词
PROTEIN-TYROSINE-PHOSPHATASE; CAUSE NOONAN; BINDING PROTEIN; MOUSE MODEL; ACTIVATION; GERMLINE; GAB1; CONSEQUENCES; GENE; RAS;
D O I
10.1128/MCB.00646-09
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 3 beta (GSK-3 beta) 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-3 beta 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-3 beta stimulation through impaired GAB1 dephosphorylation, resulting in deregulation of a novel signaling pathway that could be involved in LS pathology.
引用
收藏
页码:2498 / 2507
页数:10
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