Successive phosphorylation of p27(KIP1) protein at serine-10 and C terminus crucially controls its potency to inactivate Cdk2.

The Journal of Biological Chemistry
Atish R MohantyHiroto Okayama

Abstract

During the G(1)-S transition, the activity of Cdk2 is regulated by its association with p27(KIP1), which in rodent fibroblasts undergoes phosphorylation mainly at serine 10, threonine 187, and C-terminal threonine 197 by KIS, Cdk2, and Pim or ROCK, respectively. Recently Cdc6 the AAA+ ATPase, identified initially to assemble pre-replicative complexes on origins of replication and later to activate p21(CIP1)-inactivated Cdk2, was found also to activate p27-bound Cdk2 but only after the bound p27 is C-terminally phosphorylated. On the other hand, the biological significance of the serine 10 phosphorylation remains elusive aside from its involvement in the stability of p27 itself. We report here that serine 10 phosphorylation is required for efficient C-terminal phosphorylation of its own by PIM and ROCK kinases and critically controls the potency of p27 as a Cdk2 inhibitor. In vitro, PIM1 and active ROCK1 efficiently phosphorylated free as well as Cdk2-bound p27 but only when the p27 was phosphorylated at Ser-10 in advance. Consistently, a Ser-10 nonphosphorylatable mutant p27 protein was not phosphorylated at the C terminus in vivo. Furthermore, when double-phosphorylated, free p27 was no longer a potent inhibitor of Cdk2, and C...Continue Reading

References

Aug 1, 1994·Genes & Development·H ZhangD Beach
Dec 31, 1998·Genes & Development·L HengstS I Reed
Nov 13, 1999·Nature Cell Biology·A C CarranoM Pagano
Aug 31, 2000·Annual Review of Biochemistry·T J Kelly, G W Brown
Mar 16, 2002·Oncogene·Shigeki JinnoHiroto Okayama
Mar 11, 2004·The Journal of Biological Chemistry·Xiaobing DengEileen Friedman
Mar 17, 2004·Nature Structural & Molecular Biology·Eilyn R LacyRichard W Kriwacki
Mar 16, 2007·Cell Cycle·Tarek AbbasAnindya Dutta
Mar 22, 2008·Proceedings of the National Academy of Sciences of the United States of America·Qiuming KanHiroto Okayama
May 7, 2008·The Journal of Biological Chemistry·Qiuming KanHiroto Okayama
Jul 19, 2008·Cellular and Molecular Life Sciences : CMLS·J Vervoorts, B Lüscher
May 15, 2009·Cell Cycle·Kathleen R NevisJeanette Gowen Cook
Aug 24, 2010·Current Opinion in Cell Biology·Hiroyuki Araki
Jan 10, 2012·The Journal of Biological Chemistry·Baasanjav UranbilegHiroto Okayama

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.