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PMID: 17110335 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Role for the PP2A/B56delta phosphatase in regulating 14-3-3 release from Cdc25 to control mitosis.

Cell ·Vol. 127 ·No. 4 ·2006-11-17 ·Pages 759-73

Margolis SS, Perry JA, Forester CM, Nutt LK, Guo Y, Jardim MJ, Thomenius MJ, Freel CD, Darbandi R, Ahn JH, Arroyo JD, Wang XF, Shenolikar S, Nairn AC, Dunphy WG, Hahn WC, Virshup DM, Kornbluth S

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.

MeSH Terms
14-3-3 Proteins/metabolism Animals Checkpoint Kinase 1 DNA Replication Enzyme Activation HCT116 Cells HeLa Cells Holoenzymes/metabolism Humans Intermediate Filaments/metabolism Interphase Keratins/metabolism Mitosis Phosphoprotein Phosphatases/metabolism Phosphorylation Phosphothreonine/metabolism Protein Kinases/metabolism Protein Phosphatase 2 Protein Subunits/metabolism Xenopus/metabolism Xenopus Proteins/metabolism cdc25 Phosphatases/metabolism
Chemicals
14-3-3 Proteins Holoenzymes Protein Subunits Xenopus Proteins Phosphothreonine Keratins Protein Kinases Checkpoint Kinase 1 B56delta phosphatase, Xenopus Phosphoprotein Phosphatases Protein Phosphatase 2 cdc25 Phosphatases
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Margolis Seth S
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
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
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
0092-8674
DOI
10.1016/j.cell.2006.10.035
Published
2006-11-17
Pages
759-73
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2789796
Subset
IM
Grants
NCI NIH HHS · P01 CA50661 · United States
NCI NIH HHS · P01 CA050661-190009 · United States
NIGMS NIH HHS · R01 GM067225 · United States
NCI NIH HHS · P01 CA073992 · United States
NIGMS NIH HHS · R01 GM067225-03 · United States
NIGMS NIH HHS · R01 GM 070891 · United States
NIDA NIH HHS · P01 DA010044 · United States
NIGMS NIH HHS · R01 GM 067225 · United States
NCI NIH HHS · P01 CA050661 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2006.10.035 PMC Full Text View journal details
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