Congenital heart disease (CHD) is the most common type of birth defect worldwide. Mutations in PTPN11, the gene encoding the protein tyrosine phosphatase (PTP) Shp2, are directly implicated in CHD, causing ~50% of Noonan Syndrome (NS) and nearly all LEOPARD Syndrome (LS) cases. Both autosomal dominant, NS and LS are allelic variant disorders that have several phenotypic characteristics in common, including cardiac defects. Despite these similarities, the biochemical properties of Shp2 phosphatase function between NS and LS are very different;whereas PTPN11 NS mutations are gain-of-function "activating" mutations, LS mutations are loss-of-function and behave as "dominant negatives." Precisely how opposing PTP catalytic functions lead to such similar disease etiologies remains unknown. We propose that differences in NS and LS are mediated by phosphatase-dependent functions, whereas similarities are mediated by phosphatase- independent functions in PTPN11. We hypothesize that LS mutations evoke both phosphatase- dependent and -independent functions of Shp2 to induce aberrant signaling effects during cardiac development that lead to the onset of hypertrophic cardiomyopathy (HCM). To address this directly, we generated inducible "knockin" mice expressing the LS-associated Ptpn11 Y279C mutation. When crossed to deleter-Cre, these Shp2LS/+ mice recapitulate nearly all aspects of the human LS phenotype, including progressive HCM. Importantly, Shp2LS/+ mice show LS mutations are catalytically inactive in vivo. Therefore, as expected, there are aberrantly regulated phosphatase-dependent mechanisms associated with LS. Heart lysates from Shp2LS/+ mice have abrogated agonist-evoked Erk/Mapk activity, in contrast to Shp2NS/+ mice, whose heart lysates show elevated Erk/Mapk signaling. Moreover, Shp2LS/+, but not Shp2NS/+, heart lysates have elevated basal and agonist-induced Akt and mTor activity. However, these differences do not account for the similarities in LS and NS phenotypes. We propose that phosphatase-independent signaling must also exist and contribute to the cardiac defects in NS and LS. Indeed, with our established mouse model systems on hand (LS, Shp2 heterozygous null, Shp2 floxed, and NS mice), we have the unique opportunity to parse phosphatase-dependent vs. -independent roles for Shp2 in LS by investigating the signaling similarities/differences in LS and NS during cardiac development. We propose to 1) determine (and compare to NS) the in-vivo effects of LS expression in lineage-specific cell types during cardiac development and 2) parse the phosphatase-dependent vs. -independent contributions of Shp2 in the heart. We expect our complementary in-vivo, ex-vivo and in-vitro analyses will 1) provide novel insights into the function of Shp2 (and its mutations) in the developing heart;2) elucidate the functional mechanisms and signaling pathways involved in development of congenital HCM, and 3) suggest potential novel therapies, not only for NS and LS, but for patients with other types of CHD as well.
Our complementary in-vivo, ex-vivo and in-vitro analyses will 1) provide new insights into the function of Shp2 (PTPN11) during normal and pathological cardiac development;2) elucidate functional mechanisms and signaling pathways aberrantly regulated in NS and LS;and 3) may suggest new therapeutic approaches for treatment of patients with these disorders. Moreover, we expect our work will have important implications in congenital HCM and will yield new insights into CHD pathogenesis.
|Wang, Jianxun; Mizui, Masayuki; Zeng, Li-Fan et al. (2016) Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus. J Clin Invest 126:2077-92|
|Lauriol, Jessica; Cabrera, Janel R; Roy, Ashbeel et al. (2016) Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines. J Clin Invest 126:2989-3005|
|Breitkopf, Susanne B; Yang, Xuemei; Begley, Michael J et al. (2016) A Cross-Species Study of PI3K Protein-Protein Interactions Reveals the Direct Interaction of P85 and SHP2. Sci Rep 6:20471|
|Hahn, Andreas; Lauriol, Jessica; Thul, Josef et al. (2015) Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: palliative treatment with a rapamycin analog. Am J Med Genet A 167A:744-51|
|Korf, Bruce; Ahmadian, Reza; Allanson, Judith et al. (2015) The third international meeting on genetic disorders in the RAS/MAPK pathway: towards a therapeutic approach. Am J Med Genet A 167A:1741-6|
|Lauriol, Jessica; JaffrÃ©, Fabrice; Kontaridis, Maria I (2015) The role of the protein tyrosine phosphatase SHP2 in cardiac development and disease. Semin Cell Dev Biol 37:73-81|
|Lauriol, Jessica; Keith, Kimberly; JaffrÃ©, Fabrice et al. (2014) RhoA signaling in cardiomyocytes protects against stress-induced heart failure but facilitates cardiac fibrosis. Sci Signal 7:ra100|
|Kontaridis, Maria I (2014) How to get a K award: it is not just about the science. Circ Res 114:941-3|
|Paardekooper Overman, Jeroen; Yi, Jae-Sung; Bonetti, Monica et al. (2014) PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice. Mol Cell Biol 34:2874-89|