Proteomic Studies of PP2A-B56γ1 Phosphatase Complexes Reveal Phosphorylation-Regulated Partners in Cardiac Local Signaling

Defects of kinase-phosphatase signaling in cardiac myocytes contribute to human heart disease. The activity of one phosphatase, PP2A, is governed by B targeting subunits, including B56γ1, expressed in heart cells. As the role of PP2A/B56γ1 on the heart function remains largely unknown, this study sought to identify protein partners through unbiased, affinity purification-based proteomics combined with the functional validation. The results reveal multiple interactors that are localized in strategic cardiac sites to participate in Ca2+ homeostasis and gene expression, exemplified by the Ca pump, SERCA2a, and the splicing factor ASF/SF2. These results are corroborated by confocal imaging where adenovirally overexpressed B56γ1 is found in z-line/t-tubule region and nuclear speckles. Importantly, overexpression of B56γ1 in cultured myocytes dramatically impairs cell contractility. These results provide a global view of B56γ1-regulated local signaling and heart function. Keywords: B56γ1 • phosphatase • PP2A • proteomics • cardiac function • heart disease • signal transduction • splicing • EC coupling