Role of the Holoenzyme PP1-SPN in the Dephosphorylation of the RB Family of Tumor Suppressors During Cell Cycle.

Eva M Verdugo-Sivianes,Amancio Carnero

doi:10.3390/cancers13092226

Abstract

Simple SummaryCell cycle progression is highly regulated by modulating the phosphorylation status of retinoblastoma (RB) family proteins. This process is controlled by a balance in the action of kinases, such as the complexes formed by cyclin-dependent kinases (CDKs) and cyclins, and phosphatases, mainly the protein phosphatase 1 (PP1). However, while the phosphorylation of the RB family has been largely studied, its dephosphorylation is less known. Recently, the PP1-Spinophilin (SPN) holoenzyme has been described as the main phosphatase responsible for the dephosphorylation of RB proteins during the G0/G1 transition and at the end of G1. Here, we describe the regulation of the phosphorylation status of RB family proteins, giving importance not only to their inactivation by phosphorylation but also to their dephosphorylation to restore the cell cycle.Cell cycle progression is highly regulated by modulating the phosphorylation status of the retinoblastoma protein (pRB) and the other two members of the RB family, p107 and p130. This process is controlled by a balance in the action of kinases, such as the complexes formed by cyclin-dependent kinases (CDKs) and cyclins, and phosphatases, mainly the protein phosphatase 1 (PP1). However, while the phosphorylation of the RB family has been largely studied, its dephosphorylation is less known. Phosphatases are holoenzymes formed by a catalytic subunit and a regulatory protein with substrate specificity. Recently, the PP1-Spinophilin (SPN) holoenzyme has been described as the main phosphatase responsible for the dephosphorylation of RB proteins during the G0/G1 transition and at the end of G1. Moreover, SPN has been described as a tumor suppressor dependent on PP1 in lung and breast tumors, where it promotes tumorigenesis by increasing the cancer stem cell pool. Therefore, a connection between the cell cycle and stem cell biology has also been proposed via SPN/PP1/RB proteins.

Highlights

During tumor development, cells undergo a series of genetic and/or epigenetic alterations, which gives them selective advantages over the environment, generating cancer cells
The R point is controlled by the phosphorylation status of the retinoblastoma protein, a tumor suppressor protein whose main function is to inhibit cell cycle progression in G1 by binding E2F transcription factors and, repressing E2F-target genes necessary to advance the cell cycle
We describe the regulation of the phosphorylation status of the pRB and the other members of the RB family of tumor suppressors to emphasize their inactivation by phosphorylation and their dephosphorylation to restore the cell cycle, two mechanisms that are frequently altered during tumorigenesis

Summary

Introduction

Cells undergo a series of genetic and/or epigenetic alterations, which gives them selective advantages over the environment, generating cancer cells. The R point is controlled by the phosphorylation status of the retinoblastoma protein (pRB), a tumor suppressor protein whose main function is to inhibit cell cycle progression in G1 by binding E2F transcription factors and, repressing E2F-target genes necessary to advance the cell cycle. Phosphorylation of the pRB inhibits its cell cycle restraining function by releasing E2F transcription factors. This phosphorylation is catalyzed by the complexes formed by cyclin-dependent kinases (CDKs) and cyclins. We describe the regulation of the phosphorylation status of the pRB and the other members of the RB family of tumor suppressors to emphasize their inactivation by phosphorylation and their dephosphorylation to restore the cell cycle, two mechanisms that are frequently altered during tumorigenesis

RB Family Proteins

Findings

Conclusions