title: New approaches to prevent LEOPARD syndrome-associated cardiac hypertrophy by specifically targeting Shp2-dependent signaling.
abstract: In LEOPARD syndrome (LS) patients, mutations in the protein tyrosine phosphatase Shp2 cause hypertrophic cardiomyopathy. The prohypertrophic effects of mutant Shp2 are mediated downstream by hyperactivation of mammalian target of rapamycin. Our goal was to further define the signaling cascade that is essential for the underlying pathomechanism, thus expanding the list of potential future therapeutic targets. Using cultured neonatal rat cardiomyocytes with adenoviral gene delivery and pharmacological inhibitors, we found that hypertrophy induced by a particularly aggressive LS mutation in Shp2 depends on hyperactivation of Akt and focal adhesion kinase as well as mammalian target of rapamycin. Dissecting domain-specific functions of Shp2 using double and truncation mutants, we determined that the hypertrophic effects of mutant Shp2 depend on the two SH2 domains and on an intact catalytic center. The latter finding prompted us to test the efficacy of a Shp2 inhibitor targeted directly at the catalytic pocket. This compound, PHPS1, effectively prevented mutant Shp2-induced hypertrophy. In summary, we identified three novel targets for pharmacological therapy of LS-associated cardiac hypertrophy. Of particular importance is the finding that intervention directly at the mutant Shp2 protein is effective because this would facilitate custom-tailored therapeutic approaches for patients carrying LS mutations in Shp2.
authors.affiliation: Department of Medical Pharmacology and Physiology, Dalton Cardiovascular Research Center, University of Missouri Columbia, Columbia, Missouri 65211, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Schramm
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Edwards
authors.forename: Maike
authors.initials: M
authors.lastname: Krenz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001557:Benzenesulfonates / Q000494:pharmacology; D015153:Blotting, Western; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D002478:Cells, Cultured; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D044542:LEOPARD Syndrome / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D001557:Benzenesulfonates; D006835:Hydrazones; C529675:phenylhydrazonopyrazolone sulfonate 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: Akt; Cell Signaling; Heart; LEOPARD Syndrome; PTPN11; Phosphatase; Shp2; Signaling; Tyrosine Protein Phosphatase (Tyrosine Phosphatase); mTOR