ArticleThe Journal of biological chemistry2013
New approaches to prevent LEOPARD syndrome-associated cardiac hypertrophy by specifically targeting Shp2-dependent signaling.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- Tyrosine phosphorylation of Kir6.2 subunit negatively regulates cardiac KBasic research in cardiology · 2025Article
- Prenatal genetic diagnosis associated with fetal ventricular septal defect: an assessment based on chromosomal microarray analysis and exome sequencing.Frontiers in genetics · 2023Article
- Friend or foe? Unraveling the complex roles of protein tyrosine phosphatases in cardiac disease and development.Cellular signalling · 2022Review
- mTOR pathway in human cardiac hypertrophy caused by LEOPARD syndrome: a different role compared with animal models?Orphanet journal of rare diseases · 2019Article
- Inhibition of Shp2 ameliorates monocrotaline-induced pulmonary arterial hypertension in rats.BMC pulmonary medicine · 2018Article
- Article
- SHP2 inhibitor PHPS1 protects against atherosclerosis by inhibiting smooth muscle cell proliferation.BMC cardiovascular disorders · 2018Article
- Protein tyrosine phosphatases in cardiac physiology and pathophysiology.Heart failure reviews · 2018Review
- Heterozygous deletion of AKT1 rescues cardiac contractility, but not hypertrophy, in a mouse model of Noonan Syndrome with Multiple Lentigines.Journal of molecular and cellular cardiology · 2017Article
- Elevated Ca2+ transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines.American journal of physiology. Heart and circulatory physiology · 2015Article
- Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings.The Lancet. Respiratory medicine · 2015Article
- The Q510E mutation in Shp2 perturbs heart valve development by increasing cell migration.Journal of applied physiology (Bethesda, Md. : 1985) · 2015Article
- The role of tyrosine phosphatase Shp2 in spermatogonial differentiation and spermatocyte meiosis.Asian journal of andrologyArticle
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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