Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1 |
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Authors: | Hanna Nadine Montagner Alexandra Lee Wen Hwa Miteva Maria Vidal Michel Vidaud Michel Parfait Béatrice Raynal Patrick |
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Affiliation: | INSERM U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes 4 avenue de l'Observatoire, 75270 Paris Cedex 06, France. |
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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. |
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Keywords: | EGF, epidermal growth factor IRS-1, insulin receptor substrate 1 LS, LEOPARD syndrome NS, Noonan syndrome PTP, protein tyrosine phosphatase WT, wild type |
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