共 47 条
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
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机构:
Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France

Combier, Jean-Philippe
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机构:
Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France

Nedelec, Audrey
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Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France

Bel-Vialar, Sophie
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机构:
CNRS, UMR5547, Ctr Dev Biol, F-31062 Toulouse, France Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France

Metrich, Melanie
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Univ Paris 11, INSERM, UMRS Signalisat & Physiopathol Cardiaque 769, F-92296 Chatenay Malabry, France Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France

Conte-Auriol, Francoise
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Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France
CHRU, F-31059 Toulouse, France
Univ Toulouse 3, Hop Purpan, F-31059 Toulouse, France Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France

Lyonnet, Stanislas
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机构:
Univ Paris 05, F-75743 Paris, France
Hop Necker Enfants Malad, INSERM, U781, F-75743 Paris, France Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France

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Tauber, Maithe
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Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France
CHRU, F-31059 Toulouse, France
Univ Toulouse 3, Hop Purpan, F-31059 Toulouse, France Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France

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Lezoualc'h, Frank
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Univ Paris 11, INSERM, UMRS Signalisat & Physiopathol Cardiaque 769, F-92296 Chatenay Malabry, France Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France

Yart, Armelle
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Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France Ctr Physiopathol Toulouse Purpan, U563, INSERM, F-31024 Toulouse, France

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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.
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页码:2498 / 2507
页数:10
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US DOE, Joint Genome Inst, Walnut Creek, CA USA Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

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Digilio, Maria C.
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Bambino Gesu Pediat Hosp, Sez Genet Med, Rome, Italy Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

Martinelli, Simone
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Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

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Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

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Bartholdi, Deborah
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Univ Zurich, Inst Med Genet, CH-8603 Schwerzenbach, Switzerland Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

Kutsche, Kerstin
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Anichini, Cecilia
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Univ Siena, Dipartimento Pediat Ostetr & Med Riproduz, I-53100 Siena, Italy Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

Selicorni, Angelo
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Fdn Policlin Milano, IRCCS, Clin Pediat 1, Milan, Italy Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

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St Orsola Marcello Malpighi Hosp, Unita Operat Genet Med, Bologna, Italy Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

Tenconi, Romano
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Univ Padua, Dipartimento Pediat, I-35128 Padua, Italy Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

Zenker, Martin
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Univ Erlangen Nurnberg, Inst Human Genet, Univ Hosp Erlangen, D-8520 Erlangen, Germany Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

Merlo, Daniela
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Ist Super Sanita, Dipartimento Biol Cellulare & Neurosci, I-00161 Rome, Italy
IRCCS San Raffaele Pisana, Rome, Italy Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

Dallapiccola, Bruno
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机构:
San Giovanni Rotondo & Ist Mendel, Ist Ricovero & Cura Carattere Sci Casa Sollievo S, Rome, Italy
Univ Roma La Sapienza, Dept Expt Med, Rome, Italy Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

Iyengar, Ravi
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机构:
Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, SBCNY, New York, NY USA Ist Super Sanita, Dipartimento Ematol Oncol & Med Mol, I-00161 Rome, Italy

Bazzicalupo, Paolo
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