Low-dose dasatinib rescues cardiac function in Noonan syndrome
Jae-Sung Yi, … , Frank J. Giordano, Anton M. Bennett
Jae-Sung Yi, … , Frank J. Giordano, Anton M. Bennett
Published December 8, 2016
Citation Information: JCI Insight. 2016;1(20):e90220. https://doi.org/10.1172/jci.insight.90220.
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Research Article Cardiology Therapeutics

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 the PTPN11 gene 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 of PTPN11-related cardiomyopathies.

Authors

Jae-Sung Yi, Yan Huang, Andrea T. Kwaczala, Ivana Y. Kuo, Barbara E. Ehrlich, Stuart G. Campbell, Frank J. Giordano, Anton M. Bennett

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Figure 1

NS-induced PZR phosphorylation and the effects of dasatinib.

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NS-induced PZR phosphorylation and the effects of dasatinib. (A) Heart l...
(A) Heart lysates from WT and NS mice (D61G/+) were immunoblotted with anti-p-PZR (Y263), PZR, p-ERK1/2, ERK1/2, and SHP2 antibodies. (B) The quantitated ratios of p-PZR (Y263) to PZR and pERK1/2 to p-ERK1/2 from A normalized to the 3-week-old WT group (n = 4 per group). (C) Mouse embryonic fibroblasts from WT and NS mice were incubated with vehicle or dasatinib at the indicated concentrations for 18 hours. Whole-cell lysates were immunoblotted with anti-p-PZR (Y241), p-PZR (Y263), PZR, p-Src (Y416), Src, p-ERK1/2, ERK1/2, and SHP2 antibodies. (D) The quantitated ratios of p-PZR (Y241) to PZR, p-PZR (Y263) to PZR, p-Src (Y416) to c-Src, and p-ERK1/2 to ERK1/2 from 3 independent experiments normalized to vehicle-treated WT cells. (E) PZR and SHP2 complexes were detected by immunoprecipitation (IP) with anti-SHP2 antibodies followed by immunoblotting with anti-PZR and anti-phosphotyrosine antibodies. Immune complexes were immunoblotted with anti-SHP2 antibodies as control. Data represent mean ± SEM and were analyzed by either 2-way (B) or 1-way ANOVA and Tukey’s multiple comparison test (D). *P < 0.05; **P < 0.01; ***P < 0.001.