Glycogen synthase kinase-3 phosphorylates and regulates the stability of p27kip1 protein.
p27Kip1 is a critical regulator of the eukaryotic cell cycle. It acts as a check point protein and regulates cell cycle progression at the G1 and G1/S phase as well as predominantly blocks cell cycle progression in the absence of growth factors. Intracellular turnover of p27 is tightly regulated at the level of translation as well as by posttranslational modification. The mechanism by which p27 protein is rapidly degraded during the G1 and G1/S phase transition is well characterized. However, the process by which p27 remains extremely stable in the absence of growth factors remains unknown. Here, we report that GSK-3 dependent phosphorylation of p27 protein is essential for its enhanced stability. p27 protein harbours 2 functional GSK-3 phosphorylation sites at the C- terminus, which was found to be effectively phosphorylated by the cognate enzyme both in vitro and in vivo. Combined with earlier observation which shows that it phosphorylates and triggers cyclin D degradation; GSK-3 now appears to be a central mediator of the cell-cycle regulatory network, where it acts as a two-way switch, phosphorylating and targeting pro-proliferative factors for degradation on one hand and simultaneously phosphorylating and stabilizing an anti-proliferative factor on the other hand. This dual mode of activity may doubly ensure that cell cycle progression is aptly prohibited under conditions of limited growth factor availability.
Surjit
Milan
M
Virology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
Lal
Sunil K
SK
D000818:Animals; D002460:Cell Line; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects
D004791:Enzyme Inhibitors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D038362:Glycogen Synthase Kinase 3