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Gain-of-function mutations in SHP-2/PTPN11 cause Noonan syndrome, a human developmental disorder. Noonan syndrome is characterized by proportionate short stature, facial dysmorphia, increased risk of leukemia, and congenital heart defects in approximately 50% of cases. Congenital heart abnormalities are common in Noonan syndrome, but the signaling pathway(s) linking gain-of-function SHP-2 mutants to heart disease is unclear. Diverse cell types coordinate cardiac morphogenesis, which is regulated by calcium (Ca2+) and the nuclear factor of activated T-cells (NFAT). It has been shown that the frequency of Ca2+ oscillations regulates NFAT activity. Here, we show that in fibroblasts, Ca2+ oscillations in response to FGF-2 require the phosphatase activity of SHP-2. Conversely, gain-of-function mutants of SHP-2 enhanced FGF-2-mediated Ca2+ oscillations in fibroblasts and spontaneous Ca2+ oscillations in cardiomyocytes. The enhanced frequency of cardiomyocyte Ca2+ oscillations induced by a gain-of-function SHP-2 mutant correlated with reduced nuclear translocation and transcriptional activity of NFAT. These data imply that gain-of-function SHP-2 mutants disrupt the Ca2+ oscillatory control of NFAT, suggesting a potential mechanism for congenital heart defects in Noonan syndrome.

Gain-of-function/Noonan syndrome SHP-2/ Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling