Reduced phosphatase activity of SHP‐2 in LEOPARD syndrome: Consequences for PI3K binding on Gab1
- 12 April 2006
- journal article
- Published by Wiley in FEBS Letters
- Vol. 580 (10), 2477-2482
- https://doi.org/10.1016/j.febslet.2006.03.088
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.Keywords
This publication has 14 references indexed in Scilit:
- Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human DiseaseAmerican Journal of Human Genetics, 2006
- Diverse Biochemical Properties of Shp2 MutantsJournal of Biological Chemistry, 2005
- A Novel Role for Gab1 and SHP2 in Epidermal Growth Factor-induced Ras ActivationJournal of Biological Chemistry, 2005
- Noonan syndrome type I with PTPN11 3 bp deletion: Structure–function implicationsProteins-Structure Function and Bioinformatics, 2004
- Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activationHuman Mutation, 2004
- The ‘Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signalingTrends in Biochemical Sciences, 2003
- Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemiaNature Genetics, 2003
- Grouping of Multiple-Lentigines/LEOPARD and Noonan Syndromes on the PTPN11 GeneAmerican Journal of Human Genetics, 2002
- Receptor-Specific Regulation of Phosphatidylinositol 3′-Kinase Activation by the Protein Tyrosine Phosphatase Shp2Molecular and Cellular Biology, 2002
- A Critical Role for Phosphoinositide 3-Kinase Upstream of Gab1 and SHP2 in the Activation of Ras and Mitogen-activated Protein Kinases by Epidermal Growth FactorJournal of Biological Chemistry, 2001