Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the Aβ subunit gene

Abstract

Protein phosphatase 2A (PP2A) consists of three subunits, A, B and C. The A and B subunits have regulatory functions while C is the catalytic subunit. PP2A core enzyme is composed of subunits A and C, and the holoenzyme of subunits A, B and C. All subunits exist as multiple isoforms or splice variants. The A subunit exists as two isoforms, Aa and Ab. Here we report about the properties of eight Ab mutants, which were found in human lung and colon cancer. These mutants were reconstructed by site-directed mutagenesis and assayed for their ability to bind B and C subunits. Two mutants showed decreased binding of PR72, a member of the B'' family of B subunits, but normal C subunit binding; two mutants exhibited decreased binding of the C subunit and of B''/PR72; and one mutant showed increased binding of both the C subunit and B''/PR72. Of three mutants that behaved like the wildtype Ab subunit, one is a polymorphic variant and another one is altered outside the binding region for B and C subunits. Importantly, we also found that the wildtype Aa and Ab isoforms, although 85% identical, are remarkably di erent in their ability to bind B and C subunits. Our ®ndings may have important implications in regard to the role of PP2A as a tumor suppressor.

Reduced expression of the A? subunit of protein phosphatase 2A in human gliomas in the absence of mutations in the A? and A? subunit genes

“…[21][22][23] As in the case of A␣, most of the mutant A␤ subunits were defective in subunit interaction. 34 Therefore, it appears that A subunit function is hampered in cancer cells either as a result of gene mutation or changes in gene expression. In each case, the result is an abundance of unregulated, free C subunit.…”

PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)

“…Indeed, oncogenic mutations in the two A-subunit isoforms can differentially affect recruitment of individual B-type subunits [10,12,29,38,39] (Box 3). Structure modeling of the PR55/B subunits, which (depending on the isoform) contain four to seven degenerate WD40 repeats, reveals a toroid structure (or 'b propeller') in which four to seven twisted, antiparallel b-sheets are radially arranged around a common center (Box 1, Figure Ia).…”

“…Similar to Aa, Ab subunits harboring cancer-derived mutations display diminished capacity to bind to the C-or specific B-type subunits [30,39] and fail to rescue the transformed phenotype of cells caused by reduced Ab levels [30]. Aa expression also fails to revert the Abdependent phenotype, indicating that Aa and Ab prevent cell transformation via distinct mechanisms.…”

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

“…109,110 These mutations display defective or decreased binding to C subunit or B subunit of PP2A and therefore impair the normal functions of PP2A. 109,111,112 In addition, expression of the PP2A subunit Bg gene was found to be suppressed in human melanoma. 113 All of these findings support the notion that PP2A may function as a tumor-suppressor gene.…”