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Hyperactivation of protein phosphatase 2A in models of glucolipotoxicity and diabetes: potential mechanisms and
Anjaneyulu Kowluru1, Andrea Matti
1Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University and β-Cell Biochemistry Laboratory, John D. Dingell VA Medical Center, Detroit, MI 48201, USA. akowluru@med.wayne.edu
Abstract:
The protein phosphatase 2A [PP2A] family of enzymes has been implicated in the regulation of a variety of cellular functions including hormone secretion, growth, survival and apoptosis. PP2A accounts for ~1% of total cellular protein and ∼ 80% of total serine/threonine phosphatases, thus representing a major class of protein phosphatases in mammalian cells. Despite significant advances in our current understanding of regulation of cellular function by PP2A under physiological conditions, little is understood with regard to its regulation under various pathological conditions, such as diabetes. Emerging evidence suggests hyperactivation of PP2A in liver, muscle, retina and the pancreatic islet under the duress of glucolipotoxicity and diabetes. Interestingly, pharmacological inhibition of PP2A or siRNA-mediated depletion of the catalytic subunit of PP2A [PP2Ac] levels largely restored PP2A activity to near normal levels under these conditions. Herein, we provide an overview of PP2A subunit expression and activity in in vitro and in vivo models of glucolipotoxicity and diabetes, and revisit the existing data, which are suggestive of alterations in post-translational methylation, phosphorylation and nitration of PP2Ac under these conditions. Potential significance of hyperactive PP2A in the context of cell function, survival and apoptosis is also highlighted. It is hoped that this commentary will provide a basis for future studies to explore the potential for PP2Ac as a therapeutic target for the treatment of diabetes and other metabolic disorders.
Insights
Protein phosphatase 2A (PP2A) is hyperactivated in diabetes, impacting cellular functions. Inhibiting PP2A or its catalytic subunit (PP2Ac) may offer therapeutic benefits for metabolic disorders.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Diseases
Background:
- Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase regulating vital cellular processes.
- PP2A's role in physiological conditions is well-studied, but its function in pathological states like diabetes remains unclear.
- Emerging evidence indicates PP2A hyperactivation in key tissues affected by diabetes, such as the liver, muscle, retina, and pancreatic islets.
Purpose of the Study:
- To review PP2A subunit expression and activity in diabetes and glucolipotoxicity models.
- To examine alterations in post-translational modifications of PP2A's catalytic subunit (PP2Ac) in diabetes.
- To highlight the potential significance of hyperactive PP2A in diabetes-related cellular dysfunction and explore PP2Ac as a therapeutic target.
Main Methods:
- Review of in vitro and in vivo studies on PP2A in glucolipotoxicity and diabetes models.
- Analysis of data on PP2A subunit expression and activity.
- Examination of evidence for post-translational modifications (methylation, phosphorylation, nitration) of PP2Ac.
Main Results:
- PP2A is hyperactivated in liver, muscle, retina, and pancreatic islets under diabetic conditions (glucolipotoxicity).
- Pharmacological inhibition or siRNA-mediated depletion of PP2Ac restores PP2A activity towards normal levels.
- Altered post-translational modifications of PP2Ac are suggested in diabetes.
Conclusions:
- Hyperactivation of PP2A, particularly PP2Ac, is a significant feature of diabetes.
- Targeting PP2A or PP2Ac may represent a promising therapeutic strategy for managing diabetes and metabolic disorders.
- Further research is needed to fully elucidate PP2A's role and therapeutic potential in metabolic diseases.
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