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
Jul 25, 1996·Nature·A A RussoN P Pavletich
Jan 1, 1997·Nature Genetics·M MurphyJ Sobczak-Thépot
Dec 31, 1998·Genes & Development·L HengstS I Reed
Mar 13, 1999·Current Biology : CB·S CoatsJ M Roberts
Nov 13, 1999·Nature Cell Biology·A C CarranoM Pagano
Aug 31, 2000·Annual Review of Biochemistry·T J Kelly, G W Brown
Oct 25, 2000·Molecular and Cellular Biology·J Méndez, B Stillman
Dec 1, 2001·The EMBO Journal·G RodierS Meloche
Mar 16, 2002·Oncogene·Shigeki JinnoHiroto Okayama
Jul 3, 2002·The EMBO Journal·Manfred BoehmElizabeth G Nabel
Mar 11, 2004·The Journal of Biological Chemistry·Xiaobing DengEileen Friedman
Mar 17, 2004·Nature Structural & Molecular Biology·Eilyn R LacyRichard W Kriwacki
Nov 6, 2004·The Journal of Biological Chemistry·Yojiro KotakeKeiichi I Nakayama
Jan 5, 2006·Genes & Development·Arnaud BessonJames M Roberts
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 3, 2008·Cancer Research·Daisuke MorishitaNaoya Fujita
Jul 19, 2008·Cellular and Molecular Life Sciences : CMLS·J Vervoorts, B Lüscher
Mar 27, 2009·The Journal of Biological Chemistry·Elena SotilloXavier Graña
May 15, 2009·Cell Cycle·Kathleen R NevisJeanette Gowen Cook
May 15, 2010·FEBS Letters·Shiho Arakawa-TakeuchiHiroto Okayama
Aug 24, 2010·Current Opinion in Cell Biology·Hiroyuki Araki
Nov 19, 2010·Cell Cycle·Xuening WangGeorge P Studzinski
Nov 23, 2010·Cell Cycle·Cara L LunnJoseph J Baldassare
May 13, 2011·The Journal of Biological Chemistry·Jung-ha ParkHiroto Okayama
Jan 10, 2012·The Journal of Biological Chemistry·Baasanjav UranbilegHiroto Okayama
Citations
Aug 22, 2012·Journal of Biochemistry·Hiroto Okayama
May 1, 2013·Biochemistry·Stephan C JahnBrian K Law
Dec 9, 2014·Cell Cycle·Debora BencivengaAdriana Borriello
Apr 24, 2012·Cellular Signalling·Hiroto Okayama
Oct 12, 2016·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Hiroto Okayama
Nov 1, 2016·Nature Medicine·Dai HoriuchiAndrei Goga
Nov 10, 2017·The Journal of Biological Chemistry·Chi-Wai ChengEric Tse
Aug 27, 2015·Oncotarget·Na ZhouJason J Chen