Abstract
Noonan syndrome with multiple lentigines (NSML) is a rare autosomal dominant disorder that presents with cardio-cutaneous-craniofacial defects. Hypertrophic cardiomyopathy (HCM) represents the major life-threatening presentation in NSML. Mutations in the PTPN11 gene that encodes for the protein tyrosine phosphatase (PTP), SHP2, represents the predominant cause of HCM in NSML. NSML-associated PTPN11 mutations render SHP2 catalytically inactive with an "open" conformation. NSML-associated PTPN11 mutations cause hypertyrosyl phosphorylation of the transmembrane glycoprotein, protein zero-related (PZR), resulting in increased SHP2 binding. Here we show that NSML mice harboring a tyrosyl phosphorylation-defective mutant of PZR (NSML/PZRY242F) that is defective for SHP2 binding fail to develop HCM. Enhanced AKT/S6 kinase signaling in heart lysates of NSML mice was reversed in NSML/PZRY242F mice, demonstrating that PZR/SHP2 interactions promote aberrant AKT/S6 kinase activity in NSML. Enhanced PZR tyrosyl phosphorylation in the hearts of NSML mice was found to drive myocardial fibrosis by engaging an Src/NF-κB pathway, resulting in increased activation of IL-6. Increased expression of IL-6 in the hearts of NSML mice was reversed in NSML/PZRY242F mice, and PZRY242F mutant fibroblasts were defective for IL-6 secretion and STAT3-mediated fibrogenesis. These results demonstrate that NSML-associated PTPN11 mutations that induce PZR hypertyrosyl phosphorylation trigger pathophysiological signaling that promotes HCM and cardiac fibrosis.
Highlights
Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disorder that is characterized by left ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis [1,2,3]
Our findings suggested the involvement of aberrant protein zero-related (PZR)/Noonan syndrome with multiple lentigines (NSML)-SH2 domain–containing protein tyrosine phosphatase 2 (SHP2) interactions in NSML-associated HCM, it was not definitively addressed as to whether PZR hypertyrosyl phosphorylation and enhanced PZR/SHP2 binding are essential to the development and/or progression of congenital heart disease in general and HCM in NSML mice
To investigate the role of PZR tyrosyl phosphorylation and PZR/SHP2 binding in NSML pathogenesis, we generated a tyrosyl phosphorylation–defective PZR-knockin mutant mouse
Summary
Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disorder that is characterized by left ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis [1,2,3]. Most familial HCM is caused by mutations in genes that encode for sarcomeric proteins, such as myosin subunits, myosin binding proteins, and filament proteins, a variety of disorders exhibit apparent left ventricular hypertrophy in nonsarcomeric proteins [4]. 85% of NSML cases exhibit cardiac defects that include HCM and pulmonary stenosis. Up to 85% of patients with NSML have mutations in the PTPN11 gene, which encodes for the SH2 domain–containing protein tyrosine phosphatase 2 (SHP2) [7,8,9]. The “closed” conformation, which is mediated by the interaction between the SH2 and phosphatase domains, is destabilized by the engagement of the N-terminal SH2 domain to phosphotyrosine peptides, resulting in an “open” conformation that renders the catalytic domain substrate accessible [14, 15]
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