Role for the PP2A/B56delta phosphatase in regulating 14-3-3 release from Cdc25 to control mitosis |
| |
Authors: | Margolis Seth S Perry Jennifer A Forester Craig M Nutt Leta K Guo Yanxiang Jardim Melanie J Thomenius Michael J Freel Christopher D Darbandi Rashid Ahn Jung-Hyuck Arroyo Jason D Wang Xiao-Fan Shenolikar Shirish Nairn Angus C Dunphy William G Hahn William C Virshup David M Kornbluth Sally |
| |
Institution: | Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. |
| |
Abstract: | DNA-responsive checkpoints prevent cell-cycle progression following DNA damage or replication inhibition. The mitotic activator Cdc25 is suppressed by checkpoints through inhibitory phosphorylation at Ser287 (Xenopus numbering) and docking of 14-3-3. Ser287 phosphorylation is a major locus of G2/M checkpoint control, although several checkpoint-independent kinases can phosphorylate this site. We reported previously that mitotic entry requires 14-3-3 removal and Ser287 dephosphorylation. We show here that DNA-responsive checkpoints also activate PP2A/B56delta phosphatase complexes to dephosphorylate Cdc25 at a site distinct from Ser287 (T138), the phosphorylation of which is required for 14-3-3 release. However, phosphorylation of T138 is not sufficient for 14-3-3 release from Cdc25. Our data suggest that creation of a 14-3-3 "sink," consisting of phosphorylated 14-3-3 binding intermediate filament proteins, including keratins, coupled with reduced Cdc25-14-3-3 affinity, contribute to Cdc25 activation. These observations identify PP2A/B56delta as a central checkpoint effector and suggest a mechanism for controlling 14-3-3 interactions to promote mitosis. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|