Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the A beta subunit gene.
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, A alpha and A beta. Here we report about the properties of eight A beta 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 wild-type A beta 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 wild-type A alpha and A beta isoforms, although 85% identical, are remarkably different in their ability to bind B and C subunits. Our findings may have important implications in regard to the role of PP2A as a tumor suppressor.
Ruediger
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Department of Pathology, University of California at San Diego, La Jolla, California, CA 92093, USA.
Pham
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Walter
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D000595:Amino Acid Sequence; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000517:prevention & control; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000517:prevention & control; D008969:Molecular Sequence Data; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D054648:Protein Phosphatase 2; D021122:Protein Subunits
D007527:Isoenzymes; D021122:Protein Subunits; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2