title: Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1.
abstract: LEOPARD (LS) and Noonan (NS) are overlapping syndromes associated with distinct mutations of SHP-2. Whereas NS mutations enhance SHP-2 catalytic activity, we show that the activity of three representative LS mutants is undetectable when assayed using a standard protein tyrosine phosphatase (PTP) substrate. A different assay using a specific SHP-2 substrate confirms their decreased PTP activity, but also reveals a significant activity of the T468M mutant. In transfected cells stimulated with epidermal growth factor, the least active LS mutants promote Gab1/PI3K binding, validating our in vitro data. LS mutants thus display a reduced PTP activity both in vitro and in transfected cells.
authors.affiliation: INSERM U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes 4 avenue de l'Observatoire, 75270 Paris Cedex 06, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hanna
authors.forename: Alexandra
authors.initials: A
authors.lastname: Montagner
authors.forename: Wen Hwa
authors.initials: WH
authors.lastname: Lee
authors.forename: Maria
authors.initials: M
authors.lastname: Miteva
authors.forename: Michel
authors.initials: M
authors.lastname: Vidal
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.forename: Béatrice
authors.initials: B
authors.lastname: Parfait
authors.forename: Patrick
authors.initials: P
authors.lastname: Raynal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002384:Catalysis; D002522:Chlorocebus aethiops; D004815:Epidermal Growth Factor / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044542:LEOPARD Syndrome / Q000201:enzymology*; D008958:Models, Molecular; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004815:Epidermal Growth Factor; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C098587:GAB1 protein, human; C516724:PTPN11 protein, human