Abstract 141: Deletion of Ptpn11 (Shp2) in Cardiomyocytes Leads to Dilated Cardiomyopathy
Heart failure is the leading cause of death in the U.S. Delineating the pathways that regulate cardiomyocyte function is essential to understanding the pathogenesis of cardiac disease. Many cardiomyocyte signaling pathways activate protein tyrosine kinases, yet the role of protein tyrosine phosphatases (PTPs) in the heart is unknown. Here, we show that mice with cardiac-specific deletion of Ptpn11, the gene encoding the SH2 domain-containing PTP Shp2, rapidly develop a compensated dilated cardiomyopathy without an intervening hypertrophic phase. Primary Shp2 deficient cardiomyocytes are defective in Erk/MAPK activation in response to a variety of soluble agonists and pressure overload. Our results identify Shp2 as the first PTP known to have a critical role in cardiac function, suggest that Shp2’s cardio-protective role is mediated via control of the Erk/MAPK pathway, and have important implications for the pathogenesis of cardiac defects in the human genetic diseases Noonan Syndrome and LEOPARD Syndrome, which are caused by PTPN11 mutations.