title: Microcystin-LR (MCLR) induces a compensation of PP2A activity mediated by α4 protein in HEK293 cells.
abstract: Protein phosphatase 2A (PP2A) is a major protein phosphatase with important cell functions. Known and utilized as a potent inhibitor of PP2A, microcystin-LR (MCLR) targets PP2A as a core element that affects numerous cellular mechanisms. But apart from direct inhibition, the exact effect of MCLR on PP2A in cell is largely unknown, specifically with regard to cellular response and autoregulation. Here, we show that a low concentration of MCLR stimulates, rather than inhibits, PP2A activity in HEK293 cells. Immunoprecipitation and immunofluorescence assays reveal that the catalytic subunit and a regulatory subunit of PP2A, termed α4, dissociate from inactive complex upon MCLR exposure, suggesting that the released catalytic subunit regains activity and thereby compensates the activity loss. At high concentrations of MCLR, PP2A activity decreases along with dissociation of the core enzyme and altered post-translational modification of its catalytic subunit. In addition, the dissociation of α4 and PP2A may contribute to destabilization of HEK293 cells cytoskeleton architecture, detachment to extracellular matrix and further anoikis. Our data provide a novel PP2A upregulation mechanism and challenge the recognition of MCLR only as a PP2A inhibitor in cells.
authors.affiliation: Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Tan
authors.initials: T
authors.lastname: Li
authors.forename: Pu
authors.initials: P
authors.lastname: Huang
authors.forename: Jing
authors.initials: J
authors.lastname: Liang
authors.forename: Wenyu
authors.initials: W
authors.lastname: Fu
authors.forename: Zonglou
authors.initials: Z
authors.lastname: Guo
authors.forename: Lihong
authors.initials: L
authors.lastname: Xu
mesh_terms: D023102:Anoikis / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008387:Marine Toxins; D052998:Microcystins / Q000633:toxicity*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011499:Protein Processing, Post-Translational
chemical_list: D008387:Marine Toxins; D052998:Microcystins; D054648:Protein Phosphatase 2; C057862:cyanoginosin LR