All roads lead to PP2A: exploiting the therapeutic potential of this phosphatase

Abstract

Protein phosphatase 2A is a serine/threonine phosphatase involved in the regulation of many cellular processes. A confirmed tumor suppressor protein, PP2A is genetically altered or functionally inactivated in many cancers highlighting a need for its therapeutic reactivation. In this review we will discuss recent literature on PP2A: the elucidation of its structure and the functions of its subunits, and the identification of molecular lesions and post-translational modifications leading to its dysregulation in cancer. A final section will discuss the proteins and small molecules that modulate PP2A and how these might be used to target dysregulated forms of PP2A to treat cancers and other diseases.

Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth

“…Specific protein phosphatases, such as protein phosphatase 2A (PP2A), act as critical negative regulators of oncogenic signaling and are modulated by physiological and pathological mechanisms (3)(4)(5). PP2A is a serine/threonine phosphatase that controls many cellular functions, such as cell cycle, growth, metabolism, and apoptosis (6).…”

“…Signaling via MAPK and PI3K/ AKT pathways is regulated, in part, by PP2A, which dephosphorylates and inactivates multiple protein kinases. As a tumor suppressor gene, PP2A is genetically altered or functionally inactivated in many cancers (11)(12)(13)(14)(15), and activation of PP2A represents a promising strategy for therapeutic intervention (5).…”

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

“…The impact of these maladaptive changes in the brain is profound considering that PP2A is the master regulator of the cellular phospho‐regulatory network and plays key roles in regulating cytoskeletal integrity and signal transduction 26, 27, 28. Considering the deleterious consequences of a dysfunctional PP2A, it is unlikely that the changes observed in these postmortem brain analyses represent a protective effect in surviving neurons.…”

A SMAP in the face for cancer

“…One such example is I 2 PP2A, also known as SET, an endogenous protein inhibitor of PP2A. SET is overexpressed in human cancers, including chronic myeloid leukemia as well as colorectal, breast, and lung cancers (11). Translocation of the human gene encoding SET has also been linked to leukemia.…”