Gain-of-function/Noonan syndrome SHP-2/Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling.
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.
Uhlén
Per
P
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. per.uhlen@ki.se
Burch
Peter M
PM
Zito
Christina Ivins
CI
Estrada
Manuel
M
Ehrlich
Barbara E
BE
Bennett
Anton M
AM
D021581:Active Transport, Cell Nucleus; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006349:Heart Valve Diseases / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009634:Noonan Syndrome / Q000235:genetics / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013489:Suppression, Genetic; D014158:Transcription, Genetic
D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; D016222:Fibroblast Growth Factor 2; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C516727:Ptpn11 protein, rat