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The B56γ3 regulatory subunit-containing protein phosphatase 2A outcompetes Akt to regulate p27KIP1 subcellular localization by selectively dephosphorylating phospho-Thr157 of p27KIP1.
- Source :
-
Oncotarget [Oncotarget] 2016 Jan 26; Vol. 7 (4), pp. 4542-58. - Publication Year :
- 2016
-
Abstract
- The B56γ-containing protein phosphatase 2A (PP2A-B56γ) has been postulated to have tumor suppressive functions. Here, we report regulation of p27KIP1 subcellular localization by PP2A-B56γ3. B56γ3 overexpression enhanced nuclear localization of p27KIP1, whereas knockdown of B56γ3 decreased p27KIP1 nuclear localization. B56γ3 overexpression decreased phosphorylation at Thr157 (phospho-Thr157), whose phosphorylation promotes cytoplasmic localization of p27KIP1, whereas B56γ3 knockdown significantly increased the level of phospho-Thr157. In vitro, PP2A-B56γ3 catalyzed dephosphorylation of phospho-Thr157 in a dose-dependent and okadaic acid-sensitive manner. B56γ3 did not increase p27KIP1 nuclear localization by down-regulating the upstream kinase Akt activity and outcompeted a myristoylated constitutively active Akt (Aktca) in regulating Thr157 phosphorylation and subcellular localization of p27KIP1. In addition, results of interaction domain mapping revealed that both the N-terminal and C-terminal domains of p27 and a domain at the C-terminus of B56γ3 are required for interaction between p27 and B56γ3. Furthermore, we demonstrated that p27KIP1 levels are positively correlated with B56γ levels in both non-tumor and tumor parts of a set of human colon tissue specimens. However, positive correlation between nuclear p27KIP1 levels and B56γ levels was found only in the non-tumor parts, but not in tumor parts of these tissues, implicating a dysregulation in PP2A-B56γ3-regulated p27KIP1 nuclear localization in these tumor tissues. Altogether, this study provides a new mechanism by which the PP2A-B56γ3 holoenzyme plays its tumor suppressor role.
- Subjects :
- Animals
Blotting, Western
Cell Nucleus metabolism
Cells, Cultured
Cytoplasm metabolism
Fluorescent Antibody Technique
HeLa Cells
Humans
Mice
NIH 3T3 Cells
Phosphorylation
Subcellular Fractions
Biomarkers, Tumor metabolism
Colonic Neoplasms metabolism
Cyclin-Dependent Kinase Inhibitor p27 metabolism
Gene Expression Regulation, Neoplastic
Protein Phosphatase 2 metabolism
Proto-Oncogene Proteins c-akt metabolism
Threonine metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26684356
- Full Text :
- https://doi.org/10.18632/oncotarget.6609