Structural Studies of Shp2 mutants

• Grant number: 11/01538-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2011
• End date: April 30, 2013
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Kleber Gomes Franchini
• Grantee: Talita Miguel Marin
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Campinas , SP, Brazil
• Associated research grant: 06/54878-3 - Pathogenesis of cardiac hypertrophy and failure: mechanisms activated by mechanical stress, AP.TEM

Abstract

Germline mutations in Shp2 gene cause Noonan Syndrome (NS) and LEOPARD syndrome (LS), genetic disorders that include heart defects and increased propensity to cancer,amoung its clinical manifestations. We showed earlier that Shp2 associates and negatively regulates FAK activity in cardiomyocytes, and directly interacts with FAK in vitro. We have seen that the modulation of FAK activity by Shp2 is critical for hypertrophic signaling in cardiomyocytes. In another study, we showed that in knockin animal models mimicking NS and LS, the Shp2 was found hyper-and hypoactive, respectively, and the levels of FAK activity was opposite to Shp2 levels. We saw that in animals with NS, cardiomyocytes were thinner and smaller, whereas hypertrophied in LS. Studies of our group point to FAK as a critical signaling molecule in the cardiac hypertrophy process. FAK and Shp2 have been described as key signaling proteins in development and adult heart . However,the mechanisms by wich Shp2 interacts and regulates FAK are unknown. Given the importance of Shp2 and FAK in the signaling and in the pathophysiology of heart disease, cancer and genetic syndromes, we consider relevant the characterization of the interaction between Shp2 (wild type or carrier pathogenic mutations-NS and LS) and FAK. Moreover, available data indicate that NS and LS mutations induce a "basally-open" structural conformation in the Shp2 molecule. This assumption is based on computational modeling, made from the crystal structure of Wild Type Shp2. In the present study we will also evaluate the impact of Shp2 mutations associated with NS and LS in the protein structure