The B56gamma3 regulatory subunit of protein phosphatase 2A (PP2A) regulates S phase-specific nuclear accumulation of PP2A and the G1 to S transition.
Protein phosphatase 2A (PP2A) is a heterotrimeric enzyme consisting of a scaffold subunit (A), a catalytic subunit (C), and a variable regulatory subunit (B). The regulatory B subunits determine the substrate specificity and subcellular localization of the PP2A holoenzyme. Here, we demonstrate that the subcellular localization of the B56gamma3 regulatory subunit is regulated in a cell cycle-specific manner. Notably, B56gamma3 becomes enriched in the nucleus at the G(1)/S border and in S phase. The S phase-specific nuclear enrichment of B56gamma3 is accompanied by increases of nuclear A and C subunits and nuclear PP2A activity. Overexpression of B56gamma3 promotes nuclear localization of the A and C subunits, whereas silencing both B56gamma2 and B56gamma3 blocks the S phase-specific increase in the nuclear localization and activity of PP2A. In NIH3T3 cells, B56gamma3 overexpression reduces p27 phosphorylation at Thr-187, concomitantly elevates p27 protein levels, delays the G(1) to S transition, and retards cell proliferation. Consistently, knockdown of endogenous B56gamma3 expression reduces p27 protein levels and increases cell proliferation in HeLa cells. These findings demonstrate that the dynamic nuclear distribution of the B56gamma3 regulatory subunit controls nuclear PP2A activity, which regulates cell cycle controllers, such as p27, to restrain cell cycle progression, and may be responsible for the tumor suppressor function of PP2A.
Lee
Ting-Yuan
TY
Institute of Basic Medical Sciences, Cheng Kung University, Tainan 701, Taiwan.
Lai
Tai-Yu
TY
Lin
Shin-Chih
SC
Wu
Cheng-Wei
CW
Ni
In-Fan
IF
Yang
Yu-San
YS
Hung
Liang-Yi
LY
Law
Brian K
BK
Chiang
Chi-Wu
CW
D021581:Active Transport, Cell Nucleus; D000818:Animals; D020134:Catalytic Domain; D002453:Cell Cycle; D049109:Cell Proliferation; D016193:G1 Phase; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D016196:S Phase; D013347:Subcellular Fractions / Q000378:metabolism
C503981:PPP2R5C protein, human; D054648:Protein Phosphatase 2
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