title: Low-dose dasatinib rescues cardiac function in Noonan syndrome.
abstract: Noonan syndrome (NS) is a common autosomal dominant disorder that presents with short stature, craniofacial dysmorphism, and cardiac abnormalities. Activating mutations in thePTPN11gene encoding for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) causes approximately 50% of NS cases. In contrast, NS with multiple lentigines (NSML) is caused by mutations that inactivate SHP2, but it exhibits some overlapping abnormalities with NS. Protein zero-related (PZR) is a SHP2-binding protein that is hyper-tyrosyl phosphorylated in the hearts of mice from NS and NSML, suggesting that PZR and the tyrosine kinase that catalyzes its phosphorylation represent common targets for these diseases. We show that the tyrosine kinase inhibitor, dasatinib, at doses orders of magnitude lower than that used for its anticancer activities inhibited PZR tyrosyl phosphorylation in the hearts of NS mice. Low-dose dasatinib treatment of NS mice markedly improved cardiomyocyte contractility and functionality. Remarkably, a low dose of dasatinib reversed the expression levels of molecular markers of cardiomyopathy and reduced cardiac fibrosis in NS and NSML mice. These results suggest that PZR/SHP2 signaling is a common target of both NS and NSML and that low-dose dasatinib may represent a unifying therapy for the treatment ofPTPN11-related cardiomyopathies.
authors.affiliation: Department of Pharmacology.
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Yi
authors.affiliation: Department of Internal Medicine.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Kwaczala
authors.affiliation: Department of Pharmacology.
authors.forename: Ivana Y
authors.initials: IY
authors.lastname: Kuo
authors.affiliation: Department of Pharmacology.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Ehrlich
authors.affiliation: Department of Biomedical Engineering.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Campbell
authors.affiliation: Department of Internal Medicine.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Giordano
authors.affiliation: Department of Pharmacology.|Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Bennett
mesh_terms: D000818:Animals; D000069439:Dasatinib / Q000008:administration & dosage* / Q000494:pharmacology; D005355:Fibrosis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D009634:Noonan Syndrome / Q000188:drug therapy*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C526769:MPZL1 protein, mouse; D010750:Phosphoproteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D000069439:Dasatinib