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RSK promotes G2/M transition through activating phosphorylation of Cdc25A and Cdc25B
1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
Activation of the mitogen-activated protein kinase (MAPK) cascade in mammalian cell lines positively regulates the G2/M transition. The molecular mechanism underlying this biological phenomenon remains poorly understood. Ribosomal S6 kinase (RSK) is a key downstream element of the MAPK cascade. Our previous studies established roles of RSK2 in Cdc25C activation during progesterone-induced meiotic maturation of Xenopus oocytes. In this study we demonstrate that both recombinant RSK and endogenous RSK in Xenopus egg extracts phosphorylate all three isoforms of human Cdc25 at a conserved motif near the catalytic domain. In human HEK293 and PC-3mm2 cell lines, RSK preferentially phosphorylates Cdc25A and Cdc25B in mitotic cells. Phosphorylation of the RSK sites in these Cdc25 isoforms increases their M-phase-inducing activities. Inhibition of RSK-mediated phosphorylation of Cdc25 inhibits G2/M transition. Moreover, RSK is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of T359/S363 in RSK. Together, these findings indicate that RSK promotes G2/M transition in mammalian cells through activating phosphorylation of Cdc25A and Cdc25B.
Insights
Ribosomal S6 kinase (RSK) activates Cdc25A and Cdc25B, promoting cell cycle G2/M transition in mammalian cells. This RSK-mediated phosphorylation enhances M-phase-inducing activities, crucial for cell division.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The mitogen-activated protein kinase (MAPK) cascade regulates the G2/M cell cycle transition, but its precise molecular mechanisms are not fully understood.
- Ribosomal S6 kinase (RSK) is a critical downstream effector of the MAPK pathway.
- Previous research implicated RSK2 in Cdc25C activation during Xenopus oocyte maturation.
Purpose of the Study:
- To elucidate the role of RSK in regulating the G2/M cell cycle transition in mammalian cells.
- To investigate the phosphorylation of Cdc25 isoforms by RSK and its impact on M-phase-inducing activities.
Main Methods:
- Utilized recombinant and endogenous RSK in Xenopus egg extracts to study Cdc25 phosphorylation.
- Investigated RSK phosphorylation of human Cdc25 isoforms (Cdc25A, Cdc25B, Cdc25C) in HEK293 and PC-3mm2 cell lines.
- Assessed the effect of RSK-mediated phosphorylation on Cdc25 M-phase-inducing activities and G2/M transition.
Main Results:
- RSK phosphorylates human Cdc25A and Cdc25B at conserved motifs, enhancing their M-phase-inducing activities.
- RSK activity is higher in mitotic cells compared to interphase cells, indicated by RSK phosphorylation status.
- Inhibition of RSK-mediated Cdc25 phosphorylation impedes the G2/M cell cycle transition.
Conclusions:
- RSK promotes G2/M transition in mammalian cells by phosphorylating and activating Cdc25A and Cdc25B.
- RSK acts as a key regulator linking MAPK signaling to cell cycle progression through Cdc25 activation.
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