Department of Pharmacology, University of California, San Diego, San Diego, United States
Canzhao Liu
Department of Medicine, University of California, San Diego, San Diego, United States
Aparna Gudlur
Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, San Diego, United States
Joshua E Mayfield
Department of Pharmacology, University of California, San Diego, San Diego, United States
Nancy D Dalton
Department of Medicine, University of California, San Diego, San Diego, United States
Yusu Gu
Department of Medicine, University of California, San Diego, San Diego, United States
Ju Chen
Department of Medicine, University of California, San Diego, San Diego, United States
Joan Heller Brown
Department of Pharmacology, University of California, San Diego, San Diego, United States
Patrick G Hogan
Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, San Diego, United States; Program in Immunology, University of California, San Diego, San Diego, United States; Moores Cancer Center, University of California, San Diego, San Diego, United States
Sandra E Wiley
Department of Pharmacology, University of California, San Diego, San Diego, United States
Kirk L Peterson
Department of Medicine, University of California, San Diego, San Diego, United States
Department of Pharmacology, University of California, San Diego, San Diego, United States; Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, United States; Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, United States
Ca2+ signaling is important for many cellular and physiological processes, including cardiac function. Although sarcoplasmic reticulum (SR) proteins involved in Ca2+ signaling have been shown to be phosphorylated, the biochemical and physiological roles of protein phosphorylation within the lumen of the SR remain essentially uncharacterized. Our laboratory recently identified an atypical protein kinase, Fam20C, which is uniquely localized to the secretory pathway lumen. Here, we show that Fam20C phosphorylates several SR proteins involved in Ca2+ signaling, including calsequestrin2 and Stim1, whose biochemical activities are dramatically regulated by Fam20C mediated phosphorylation. Notably, phosphorylation of Stim1 by Fam20C enhances Stim1 activation and store-operated Ca2+ entry. Physiologically, mice with Fam20c ablated in cardiomyocytes develop heart failure following either aging or induced pressure overload. We extended these observations to show that non-muscle cells lacking Fam20C display altered ER Ca2+ signaling. Overall, we show that Fam20C plays an overarching role in ER/SR Ca2+ homeostasis and cardiac pathophysiology.
