Title | Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Yi, J-S, Perla, S, Enyenihi, L, Bennett, AM |
Journal | JCI Insight |
Volume | 5 |
Issue | 15 |
Date Published | 2020 08 06 |
ISSN | 2379-3708 |
Keywords | Animals, Cardiomyopathy, Hypertrophic, Disease Models, Animal, Female, Intracellular Signaling Peptides and Proteins, LEOPARD Syndrome, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Myocytes, Cardiac, Phosphoproteins, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Tyrosine |
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. |
DOI | 10.1172/jci.insight.137753 |
Alternate Journal | JCI Insight |
PubMed ID | 32584792 |
PubMed Central ID | PMC7455087 |
Grant List | R01 HL134166 / HL / NHLBI NIH HHS / United States S10 RR023602 / RR / NCRR NIH HHS / United States UM1 HG006504 / HG / NHGRI NIH HHS / United States |