PP2A Counterbalances Phosphorylation of pRB and Mitotic Proteins by Multiple CDKs: Potential Implications for PP2A Disruption in Cancer

Abstract

Protein Phosphatase 2A (PP2A) consists of a collection of heterotrimeric serine/threonine phosphatase holoenzymes that play multiple roles in cell signaling via dephosphorylation of numerous substrates of a large family of serine/threonine kinases. PP2A substrate specificity is mediated by B regulatory subunits of four different families, which selectively recognize diverse substrates by mechanisms that are not well understood. Among the many signaling pathways with critical PP2A functions are several deregulated in cancer cells, and PP2A is a know tumor suppressor. However, the precise composition of the heterotrimeric PP2A complexes with tumor supressor activity is not well understood. This review is centered on the emerging role of the B regulatory subunit B55a and related subfamilly members in the modulation of the phosphorylation state of pocket proteins and mitotic CDK substrates, as well as the implications of PP2A function disruption in cancer in the context of these activities.

Activation of p107 by Fibroblast Growth Factor, Which Is Essential for Chondrocyte Cell Cycle Exit, Is Mediated by the Protein Phosphatase 2A/B55α Holoenzyme

“…In addition, we observe more clear effects in the accumulation of cells with G 2 /M DNA contents (Fig. 7B), a finding which is consistent with the recently proposed role of these phosphatases in counteracting the action of CDK1 in modulating the phosphorylation state of mitotic substrates (4,8,40). Even when considering cells accumulating from S phase to mitosis (Fig.…”

“…One major consequence of pocket protein inactivation is the disruption of pocket protein/E2F4 repressor complexes, which results in derepression of E2F-dependent genes, including those encoding G 1 /S, S, and M cyclins as well as activator E2Fs, as cells commit to a new round of DNA replication (3,6). Although G 1 and G 1 /S CDKs become inactivated as cells progress through S phase in a cell-typedependent manner, the activation of the E2F program, the stabilization of S-M cyclins, and phosphorylation/dephosphorylation events targeting CDKs result in the sequential activation of cyclin A/CDK2 and cyclin B/CDK1 complexes that maintain pocket proteins hyperphosphorylated through the remainder of the cell cycle until late mitosis (7)(8)(9)(10), when the three pocket proteins are abruptly and coordinately dephosphorylated (11,12).…”

PP2A: The Wolf in Sheep’s Clothing?

“…Mutations in PP2A subunits have been found in a variety of human cancers and include deletions, point mutations and mutations that generate alternate transcripts [ 13 , 33 ]. Some of these mutations prevent the A subunit from binding to the B and C subunits.…”

Cancerous inhibitor of protein phosphatase 2A contributes to human papillomavirus oncoprotein E7-induced cell proliferation via E2F1

“…Cancerous inhibitor of protein phosphatase 2A (PP2A; CIP2A) was first identified as a novel endogenous interacting partner of PP2A [ 8 ], which is a serine/threonine phophatase and may function as a tumor suppressor [ 9 , 10 ]. Later CIP2A was found to be overexpressed in many human malignancies including gastric, bladder, ovarian, tongue, hepatocellular, and colon cancer as well as non-small cell lung carcinoma and chronic myelogenous leukemia (reviewed in [ 11 ]).…”