The Role and Mechanisms of Protein Phosphatase 2A (PP2A) in Cellular Regulation and Disease

Dayanara Eulalia^*
*Correspondence: Dayanara Eulalia, Department of Medicine, Downstate Health Sciences University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA, Email:

Introduction

Protein Phosphatase 2A (PP2A) is a serine/threonine phosphatase that plays a crucial role in various cellular processes. It is one of the most abundant phosphatases in eukaryotic cells, contributing to the regulation of cell growth, division and death. PP2A functions as a tumor suppressor and is involved in the negative regulation of numerous signaling pathways, making it a significant focus of research in the context of cancer and other diseases.

PP2A is a heterotrimeric enzyme composed of a catalytic subunit (C), a structural subunit (A) and a regulatory subunit (B). The A subunit, also known as PR65, acts as a scaffold, facilitating the assembly of the C and B subunits. The C subunit is the core enzyme responsible for dephosphorylation, while the B subunit determines the substrate specificity, cellular localization and regulatory functions of the holoenzyme. There are multiple isoforms of each subunit, leading to a diversity of PP2A holoenzymes with distinct functions [1].

Description

Post-translational modifications

PP2A activity and specificity are regulated by post-translational modifications (PTMs) such as phosphorylation, methylation and ubiquitination. The methylation of the C-terminal leucine residue of the C subunit by leucine carboxyl methyltransferase 1 (LCMT1) enhances the binding of certain B subunits, thus modulating PP2A activity. Conversely, phosphorylation of the catalytic subunit by protein kinases can inhibit its phosphatase activity.

Regulatory subunits

The regulatory B subunits are critical for determining PP2A’s function. There are four families of B subunits (B/B55, B’/B56, B’’/PR72 and B’’’/Striatin), each with multiple isoforms. The combination of different B subunits with the AC dimer forms distinct holoenzymes that target specific substrates, thereby regulating diverse cellular pathways [2].

Interacting proteins

PP2A interacts with a variety of proteins that can influence its activity and specificity. These include both regulatory proteins and substrate proteins. For instance, the PP2A inhibitor proteins, such as SET and CIP2A, can bind to PP2A and inhibit its activity, thus modulating its function in cellular signaling pathways.

Cell cycle regulation

PP2A plays a pivotal role in cell cycle regulation by dephosphorylating key proteins involved in cell cycle progression. It is essential for the exit from mitosis and the proper functioning of checkpoints that ensure the fidelity of cell division. PP2A dephosphorylates and inactivates cyclin-dependent kinases (CDKs) and other mitotic kinases, thereby preventing uncontrolled cell proliferation [3].

Signal transduction

PP2A is a critical regulator of multiple signaling pathways, including the MAPK, PI3K/Akt and Wnt signaling pathways. By dephosphorylating components of these pathways, PP2A acts as a negative regulator, thus maintaining cellular homeostasis. Dysregulation of PP2A activity can lead to aberrant signaling and contribute to disease development.

PP2A in disease

PP2A is frequently implicated in cancer, acting as a tumor suppressor by negatively regulating oncogenic signaling pathways. Loss of PP2A function, through mutations or the overexpression of inhibitory proteins like SET and CIP2A, can lead to uncontrolled cell growth and tumor development. Reactivating PP2A in cancer cells has emerged as a potential therapeutic strategy, with several compounds identified that can restore PP2A activity [4].

Neurodegenerative diseases

In neurodegenerative diseases such as Alzheimer's disease, altered PP2A activity has been observed. PP2A is involved in the dephosphorylation of tau protein and its dysfunction can lead to tau hyperphosphorylation, a hallmark of Alzheimer's pathology. Enhancing PP2A activity is being explored as a therapeutic approach to mitigate tau-related neurodegeneration [5].

Cardiovascular diseases

PP2A also plays a role in cardiovascular health by regulating signaling pathways involved in cardiac function. Dysregulation of PP2A activity has been linked to heart failure and arrhythmias. Targeting PP2A and its regulatory mechanisms may offer new avenues for treating cardiovascular diseases.

Therapeutic potential and challenges

The therapeutic targeting of PP2A presents both opportunities and challenges. Small molecules that activate PP2A have shown promise in preclinical studies for cancer and neurodegenerative diseases. However, the challenge lies in the specificity of these compounds, as PP2A is involved in numerous cellular processes. Understanding the precise mechanisms and context-specific roles of PP2A is essential for developing targeted therapies with minimal side effects.

Conclusion

PP2A is a vital enzyme in cellular regulation, influencing a broad spectrum of biological processes. Its role as a tumor suppressor and regulator of cell signaling highlights its importance in maintaining cellular homeostasis. Ongoing research into the mechanisms of PP2A regulation and its involvement in disease continues to uncover new insights, offering potential therapeutic avenues for a range of conditions. The complexity of PP2A regulation underscores the need for a nuanced approach in developing PP2A-targeted therapies.

Acknowledgement

None.

Conflict of Interest

None.

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