Protein phosphatase 2

Protein phosphatase 2 (PP2), also known as PP2A, is a major serine/threonine-specific protein phosphatase that plays a critical role in cellular regulation. It is involved in various cellular processes including cell growth, division, and death. PP2A is a holoenzyme that consists of a structural A subunit, a regulatory B subunit, and a catalytic C subunit. This enzyme is highly conserved across eukaryotic species, underscoring its importance in cellular physiology.

Structure

PP2A is a trimeric holoenzyme. The core enzyme comprises the A and C subunits, where the A subunit serves as a scaffolding molecule, binding both the C subunit and one of the several regulatory B subunits. The C subunit is the catalytic moiety of the enzyme. The B subunit determines the substrate specificity, cellular localization, and the regulatory properties of the holoenzyme. There are multiple isoforms of each subunit (Aα/β, B family members, and Cα/β), which allow for a diversity of PP2A complexes, each targeting different substrates and functions.

Function

PP2A is involved in the negative regulation of cell growth and division. It dephosphorylates a variety of key cellular proteins, including those involved in the signaling pathways for cell growth and apoptosis. For example, it can dephosphorylate the cyclin-dependent kinases (CDKs), which are critical for cell cycle progression. By dephosphorylating these kinases, PP2A acts as a tumor suppressor, inhibiting the uncontrolled growth of cells.

In addition to its role in cell cycle regulation, PP2A also participates in the regulation of DNA replication and repair, apoptosis, and protein synthesis. It is involved in the control of MAP kinase signaling pathways, which are important for cell response to growth factors and stress.

Regulation

The activity and specificity of PP2A are regulated by the interaction of the core enzyme with its regulatory B subunits, as well as by post-translational modifications of its subunits, such as methylation and phosphorylation. The methylation of the C subunit, for example, is essential for the binding of certain B subunits, affecting the substrate specificity and localization of the holoenzyme.

Clinical Significance

Alterations in the expression or activity of PP2A have been implicated in the development of several diseases, including cancer. Overexpression or mutations in the B subunits can lead to aberrant PP2A activity, contributing to tumorigenesis. Conversely, restoration of PP2A activity has been proposed as a therapeutic strategy in certain cancers.

PP2A also plays a role in neurodegenerative diseases. It is involved in the dephosphorylation of tau protein, and its dysfunction has been linked to Alzheimer's disease and other tauopathies.

Research Directions

Current research is focused on understanding the complex regulation of PP2A, identifying its various substrates, and exploring its role in diseases. There is also significant interest in developing PP2A as a therapeutic target, particularly in cancer and neurodegenerative diseases.