The B56γ3 regulatory subunit-containing protein phosphatase 2A outcompetes Akt to regulate p27KIP1 subcellular localization by selectively dephosphorylating phospho-Thr157 of p27KIP1
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Tai-Yu Lai1, Chia-Jui Yen2,3,*, Hung-Wen Tsai4,*, Yu-San Yang5, Wei-Fu Hong5, Chi-Wu Chiang1,5,6
1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
2Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
3Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
4Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
5Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
6Center for Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan
*These authors have contributed equally to this work
Chi-Wu Chiang, e-mail: firstname.lastname@example.org
Keywords: PP2A, B56γ3, p27, subcellular localization, Akt
Received: June 17, 2015 Accepted: December 02, 2015 Published: December 14, 2015
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.
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