Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines

JCI Insight. 2020 Aug 6;5(15):e137753. doi: 10.1172/jci.insight.137753.

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.

Keywords: Cardiology; Cardiovascular disease; Genetic diseases; Signal transduction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cardiomyopathy, Hypertrophic / etiology
  • Cardiomyopathy, Hypertrophic / metabolism
  • Cardiomyopathy, Hypertrophic / pathology*
  • Disease Models, Animal*
  • Female
  • Intracellular Signaling Peptides and Proteins / physiology*
  • LEOPARD Syndrome / complications*
  • LEOPARD Syndrome / genetics
  • LEOPARD Syndrome / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Phosphoproteins / physiology*
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics*
  • Tyrosine / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • MPZL1 protein, mouse
  • Phosphoproteins
  • Tyrosine
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse