Congenital heart defects (CHDs) are the most common type of birth defect (~1/100 live births) and the major cause of birth-related deaths. Mutations in the Ras/mitogen-activated protein kinase (MAPK) pathway known as ?RASopathies? that include Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) manifest in a variety of clinical problems but most notably, CHDs. NS and NSML patients exhibit a range of CHD-related anomalies such as pulmonic valve stenosis, hypertrophic cardiomyopathy and atrial septal defects. Approximately, 50% of NS and 90% of NSML patients have autosomal dominant mutations in PTPN11, the gene encoding the SH2 domain-containing protein tyrosine phosphatase, Shp2. NS represents the most common non-chromosomal cause of CHD. Therefore, understanding the mechanisms of NS, and subsequently NSML, will provide insight into the causation of some forms of CHD. Using an integrated set of approaches that include phospho proteomics, zebrafish genetics, biochemistry and cell biology we have identified protein zero-related (PZR), a transmembrane glycoprotein that binds Shp2, as a novel target protein involved in heart development. PZR was identified to be aberrantly increased in its levels of tyrosyl phosphorylation in the heart of mouse models of both NS and NSML suggesting that PZR is a common target of these RASopathies. Therefore, the aims of this application are to 1) define the molecular determinants governing downstream signaing of PZR and to determine how PZR serves as a common signaling target for NS and NSML, 2) test the efficacy of low-dose tyrosine kinase inhibitors to disrupt aberrant PZR/Shp2 signaling to ameliorate the development of NS- and NSML-related CHD and 3) generate novel PZR mouse models to define the contribution of PZR in the development of NS and NSML-related CHD. Collectively, these results will provide insight into common mechanisms that underlie both NS and NSML-related CHD. Finally, novel strategies for the potential treatment of NS/NSML-associated CHD will be uncovered.
Autosomal dominant mutations in the gene PTPN11 that encodes for the protein tyrosine phosphatase, Shp2, represent the largest non-chromosomal form of congenital heart disease. This application seeks to understand the signaling mechanisms through which mutated PTPN11 causes congenital heart defects and how modulation of this signaling pathway may be exploited as a therapy towards the treatment of certain forms of congenital heart disease.
| Levy, Aaron D; Xiao, Xiao; Shaw, Juliana E et al. (2018) Noonan Syndrome-Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function. Cell Rep 24:1523-1535 |
