TY - JOUR
T1 - Protein phosphatase 2A in the healthy and failing heart
T2 - New insights and therapeutic opportunities
AU - Sergienko, Nicola M.
AU - Donner, Daniel G.
AU - Delbridge, Lea M.D.
AU - McMullen, Julie R.
AU - Weeks, Kate L.
N1 - Funding Information:
NMS is supported by a Research Training Program Scholarship from the Australian Government. LMDD acknowledges the research support of the Australian Research Council and the National Health and Medical Research Council of Australia . JRM is supported by a National Health and Medical Research Council Senior Research Fellowship (grant number 1078985 ). KLW is supported by a Future Leader Fellowship from the National Heart Foundation of Australia (award ID 102539 ) and receives project support from The Shine On Foundation .
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2022/3
Y1 - 2022/3
N2 - Protein phosphatases have emerged as critical regulators of phosphoprotein homeostasis in settings of health and disease. Protein phosphatase 2A (PP2A) encompasses a large subfamily of enzymes that remove phosphate groups from serine/threonine residues within phosphoproteins. The heterogeneity in PP2A structure, which arises from the grouping of different catalytic, scaffolding and regulatory subunit isoforms, creates distinct populations of catalytically active enzymes (i.e. holoenzymes) that localise to different parts of the cell. This structural complexity, combined with other regulatory mechanisms, such as interaction of PP2A heterotrimers with accessory proteins and post-translational modification of the catalytic and/or regulatory subunits, enables PP2A holoenzymes to target phosphoprotein substrates in a highly specific manner. In this review, we summarise the roles of PP2A in cardiac physiology and disease. PP2A modulates numerous processes that are vital for heart function including calcium handling, contractility, β-adrenergic signalling, metabolism and transcription. Dysregulation of PP2A has been observed in human cardiac disease settings, including heart failure and atrial fibrillation. Efforts are underway, particularly in the cancer field, to develop therapeutics targeting PP2A activity. The development of small molecule activators of PP2A (SMAPs) and other compounds that selectively target specific PP2A holoenzymes (e.g. PP2A/B56α and PP2A/B56ε) will improve understanding of the function of different PP2A species in the heart, and may lead to the development of therapeutics for normalising aberrant protein phosphorylation in settings of cardiac remodelling and dysfunction.
AB - Protein phosphatases have emerged as critical regulators of phosphoprotein homeostasis in settings of health and disease. Protein phosphatase 2A (PP2A) encompasses a large subfamily of enzymes that remove phosphate groups from serine/threonine residues within phosphoproteins. The heterogeneity in PP2A structure, which arises from the grouping of different catalytic, scaffolding and regulatory subunit isoforms, creates distinct populations of catalytically active enzymes (i.e. holoenzymes) that localise to different parts of the cell. This structural complexity, combined with other regulatory mechanisms, such as interaction of PP2A heterotrimers with accessory proteins and post-translational modification of the catalytic and/or regulatory subunits, enables PP2A holoenzymes to target phosphoprotein substrates in a highly specific manner. In this review, we summarise the roles of PP2A in cardiac physiology and disease. PP2A modulates numerous processes that are vital for heart function including calcium handling, contractility, β-adrenergic signalling, metabolism and transcription. Dysregulation of PP2A has been observed in human cardiac disease settings, including heart failure and atrial fibrillation. Efforts are underway, particularly in the cancer field, to develop therapeutics targeting PP2A activity. The development of small molecule activators of PP2A (SMAPs) and other compounds that selectively target specific PP2A holoenzymes (e.g. PP2A/B56α and PP2A/B56ε) will improve understanding of the function of different PP2A species in the heart, and may lead to the development of therapeutics for normalising aberrant protein phosphorylation in settings of cardiac remodelling and dysfunction.
KW - Heart failure
KW - Kinases
KW - PP2A
KW - Protein phosphatase 2A
KW - Therapies
UR - http://www.scopus.com/inward/record.url?scp=85121243189&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2021.110213
DO - 10.1016/j.cellsig.2021.110213
M3 - Review Article
C2 - 34902541
AN - SCOPUS:85121243189
SN - 0898-6568
VL - 91
JO - Cellular Signalling
JF - Cellular Signalling
M1 - 110213
ER -