Overexpression of the Catalytic Subunit of Protein Phosphatase 2A Impairs Cardiac Function

Abstract

Reversible protein phosphorylation is an essential regulatory mechanism in many cellular functions. In contrast to protein kinases, the role and regulation of protein phosphatases has remained ambiguous. To address this issue, we generated transgenic mice that overexpress the catalytic subunit ␣ of protein phosphatase 2A (PP2A) (PP2Ac␣) in the heart driven by the ␣-myosin heavy chain promoter. Overexpression of the PP2Ac␣ gene in the heart led to increased levels of the transgene both at RNA and protein levels. This was accompanied by a significant increase of PP2A enzyme activity in the myocardium. Morphological analysis revealed isles of necrosis and fibrosis. The phosphorylation state of phospholamban, troponin inhibitor, and eukaryotic elongation factor 2 was reduced significantly. The expression of junctional (calsequestrin) and free SR proteins (SERCA and phospholamban) was not altered. Whereas no increase in morbidity or mortality was noted, transgenic mice developed cardiac hypertrophy and reduced contractility of the heart, as well as cardiac dilatation as shown by biplane echocardiography. Taken together, these findings are indicative of the fundamental role of PP2A in cardiac function and imply that disturbances in protein phosphatases expression and activity may cause or aggravate the course of cardiac diseases.

Protein phosphatase 2A is a negative regulator of IL-2 production in patients with systemic lupus erythematosus

“…Although overexpression of PP2Ac in a transgenic mouse led to upregulation of PP2Ac enzymatic activity (44), mutation of the catalytic site leads to increased expression of PP2A protein (45). Since phosphorylation of PP2Ac inhibits its catalytic activity (46) and SLE T cells display increased TCR/CD3-initiated phosphorylation of cytosolic proteins (47), we considered the increased protein levels of PP2Ac may represent a compensatory response to improperly phosphorylated and therefore inactive PP2Ac (46).…”

Obscure functions: the location–function relationship of obscurins

“…These findings suggest the obscurin-ankyrin-B complex is necessary for recruitment of PP2A to the Mband. PP2A, a major protein phosphatase in the heart, is responsible for modulating Ca 2+ signaling through its regulation of essential ion channels and pumps (Gergs et al 2004;Lei et al 2015Lei et al , 2016. Aberrant expression or mislocalization of PP2A is associated with cardiac pathophysiology, including heart failure and arrhythmias (Gergs et al 2004;Lei et al 2015;Li et al 2016).…”

“…PP2A, a major protein phosphatase in the heart, is responsible for modulating Ca 2+ signaling through its regulation of essential ion channels and pumps (Gergs et al 2004;Lei et al 2015Lei et al , 2016. Aberrant expression or mislocalization of PP2A is associated with cardiac pathophysiology, including heart failure and arrhythmias (Gergs et al 2004;Lei et al 2015;Li et al 2016). In addition, in C. elegans the protein phosphatase SCPL-1, which localizes to the M-band, interacts with the pseudo-kinase regions of UNC-89 (Qadota et al 2008b;Xiong et al 2009).…”

Representational difference analysis of cDNA identifies novel genes expressed following preconditioning of the heart

“…Truttmann et al (2004) demonstrated that hypoxia decreased catalytic activity and protein levels of the PP2 catalytic subunit in cerebral cortex of newborn piglets. Gergs et al, (2004) generated transgenic mice with tissue specific over-expression of the catalytic subunit alpha (PP2acaAlpha) in the heart. Over-expression led to tissue necrosis and fibrosis and altered phosphorylation of a number of PP2 target proteins.…”