Role for the PP2A/B56δ Phosphatase in Regulating 14-3-3 Release from Cdc25 to Control Mitosis

Seth S. Margolis; Jennifer A. Perry; Craig M. Forester; Leta K. Nutt; Yanxiang Guo; Melanie J. Jardim; Michael J. Thomenius; Christopher D. Freel; Rashid Darbandi; Jung Hyuck Ahn; Jason D. Arroyo; Xiao Fan Wang; Shirish Shenolikar; Angus C. Nairn; William G. Dunphy; William C. Hahn; David M. Virshup; Sally Kornbluth

doi:10.1016/j.cell.2006.10.035

Role for the PP2A/B56δ Phosphatase in Regulating 14-3-3 Release from Cdc25 to Control Mitosis

Seth S. Margolis, Jennifer A. Perry, Craig M. Forester, Leta K. Nutt, Yanxiang Guo, Melanie J. Jardim, Michael J. Thomenius, Christopher D. Freel, Rashid Darbandi, Jung Hyuck Ahn, Jason D. Arroyo, Xiao Fan Wang, Shirish Shenolikar, Angus C. Nairn, William G. Dunphy, William C. Hahn, David M. Virshup, Sally Kornbluth

Research output: Contribution to journal › Article › peer-review

149 Scopus citations

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/B56δ 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/B56δ as a central checkpoint effector and suggest a mechanism for controlling 14-3-3 interactions to promote mitosis.

Original language	English (US)
Pages (from-to)	759-773
Number of pages	15
Journal	Cell
Volume	127
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2006.10.035
State	Published - Nov 17 2006
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2006.10.035

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Margolis, S. S., Perry, J. A., Forester, C. M., Nutt, L. K., Guo, Y., Jardim, M. J., Thomenius, M. J., Freel, C. D., Darbandi, R., Ahn, J. H., Arroyo, J. D., Wang, X. F., Shenolikar, S., Nairn, A. C., Dunphy, W. G., Hahn, W. C., Virshup, D. M., & Kornbluth, S. (2006). Role for the PP2A/B56δ Phosphatase in Regulating 14-3-3 Release from Cdc25 to Control Mitosis. Cell, 127(4), 759-773. https://doi.org/10.1016/j.cell.2006.10.035

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 2006, 'Role for the PP2A/B56δ Phosphatase in Regulating 14-3-3 Release from Cdc25 to Control Mitosis', Cell, vol. 127, no. 4, pp. 759-773. https://doi.org/10.1016/j.cell.2006.10.035

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title = "Role for the PP2A/B56δ Phosphatase in Regulating 14-3-3 Release from Cdc25 to Control Mitosis",

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/B56δ 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/B56δ as a central checkpoint effector and suggest a mechanism for controlling 14-3-3 interactions to promote mitosis.",

author = "Margolis, {Seth S.} and Perry, {Jennifer A.} and Forester, {Craig M.} and Nutt, {Leta K.} and Yanxiang Guo and Jardim, {Melanie J.} and Thomenius, {Michael J.} and Freel, {Christopher D.} and Rashid Darbandi and Ahn, {Jung Hyuck} and Arroyo, {Jason D.} and Wang, {Xiao Fan} and Shirish Shenolikar and Nairn, {Angus C.} and Dunphy, {William G.} and Hahn, {William C.} and Virshup, {David M.} and Sally Kornbluth",

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doi = "10.1016/j.cell.2006.10.035",

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AU - Margolis, Seth S.

AU - Perry, Jennifer A.

AU - Forester, Craig M.

AU - Nutt, Leta K.

AU - Guo, Yanxiang

AU - Jardim, Melanie J.

AU - Thomenius, Michael J.

AU - Freel, Christopher D.

AU - Darbandi, Rashid

AU - Ahn, Jung Hyuck

AU - Arroyo, Jason D.

AU - Wang, Xiao Fan

AU - Shenolikar, Shirish

AU - Nairn, Angus C.

AU - Dunphy, William G.

AU - Hahn, William C.

AU - Virshup, David M.

AU - Kornbluth, Sally

PY - 2006/11/17

Y1 - 2006/11/17

N2 - 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/B56δ 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/B56δ as a central checkpoint effector and suggest a mechanism for controlling 14-3-3 interactions to promote mitosis.

AB - 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/B56δ 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/B56δ as a central checkpoint effector and suggest a mechanism for controlling 14-3-3 interactions to promote mitosis.

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Role for the PP2A/B56δ Phosphatase in Regulating 14-3-3 Release from Cdc25 to Control Mitosis

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