PP1 and PP2A use opposite phospho-dependencies to control distinct processes at the kinetochore

Richard Smith, Marilia Henriques Cordeiro, Norman E. Davey, Giulia Vallardi, Andrea Ciliberto, Fridolin Gross, Adrian Saurin (Lead / Corresponding author)

Research output: Contribution to journalArticle

24 Downloads (Pure)

Abstract

PP1 and PP2A-B56 are major serine/threonine phosphatase families that achieve specificity by colocalizing with substrates. At the kinetochore, however, both phosphatases localize to an almost identical molecular space and yet they still manage to regulate unique pathways and processes. By switching or modulating the positions of PP1/PP2A-B56 at kinetochores, we show that their unique downstream effects are not due to either the identity of the phosphatase or its precise location. Instead, these phosphatases signal differently because their kinetochore recruitment can be either inhibited (PP1) or enhanced (PP2A) by phosphorylation inputs. Mathematical modeling explains how these inverse phospho-dependencies elicit unique forms of cross-regulation and feedback, which allows otherwise indistinguishable phosphatases to produce distinct network behaviors and control different mitotic processes. Furthermore, our genome-wide analysis suggests that these major phosphatase families may have evolved to respond to phosphorylation inputs in opposite ways because many other PP1 and PP2A-B56-binding motifs are also phospho-regulated.

Original languageEnglish
Pages (from-to)2206-2219.e8
Number of pages22
JournalCell Reports
Volume28
Issue number8
Early online date20 Aug 2019
DOIs
Publication statusPublished - 20 Aug 2019

Fingerprint

Kinetochores
Phosphoric Monoester Hydrolases
Phosphorylation
Behavior Control
Phosphoprotein Phosphatases
Genes
Dependency (Psychology)
Genome
Feedback
Substrates

Keywords

  • Mitosis
  • SAC
  • SliM
  • kinase
  • kinetochore
  • microtubule attachment
  • phosphatase binding
  • phosphorylation
  • short linear motif
  • spindle assembly checkpoint

Cite this

@article{65185e9cccf34ee1844a45d13b052364,
title = "PP1 and PP2A use opposite phospho-dependencies to control distinct processes at the kinetochore",
abstract = "PP1 and PP2A-B56 are major serine/threonine phosphatase families that achieve specificity by colocalizing with substrates. At the kinetochore, however, both phosphatases localize to an almost identical molecular space and yet they still manage to regulate unique pathways and processes. By switching or modulating the positions of PP1/PP2A-B56 at kinetochores, we show that their unique downstream effects are not due to either the identity of the phosphatase or its precise location. Instead, these phosphatases signal differently because their kinetochore recruitment can be either inhibited (PP1) or enhanced (PP2A) by phosphorylation inputs. Mathematical modeling explains how these inverse phospho-dependencies elicit unique forms of cross-regulation and feedback, which allows otherwise indistinguishable phosphatases to produce distinct network behaviors and control different mitotic processes. Furthermore, our genome-wide analysis suggests that these major phosphatase families may have evolved to respond to phosphorylation inputs in opposite ways because many other PP1 and PP2A-B56-binding motifs are also phospho-regulated.",
keywords = "Mitosis, SAC, SliM, kinase, kinetochore, microtubule attachment, phosphatase binding, phosphorylation, short linear motif, spindle assembly checkpoint",
author = "Richard Smith and {Henriques Cordeiro}, Marilia and Davey, {Norman E.} and Giulia Vallardi and Andrea Ciliberto and Fridolin Gross and Adrian Saurin",
note = "Funding: Cancer Research UK (C47320/A21229 and C10988/A22566 to ATS)",
year = "2019",
month = "8",
day = "20",
doi = "10.1016/j.celrep.2019.07.067",
language = "English",
volume = "28",
pages = "2206--2219.e8",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "8",

}

PP1 and PP2A use opposite phospho-dependencies to control distinct processes at the kinetochore. / Smith, Richard; Henriques Cordeiro, Marilia; Davey, Norman E.; Vallardi, Giulia; Ciliberto, Andrea; Gross, Fridolin; Saurin, Adrian (Lead / Corresponding author).

In: Cell Reports, Vol. 28, No. 8, 20.08.2019, p. 2206-2219.e8.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PP1 and PP2A use opposite phospho-dependencies to control distinct processes at the kinetochore

AU - Smith, Richard

AU - Henriques Cordeiro, Marilia

AU - Davey, Norman E.

AU - Vallardi, Giulia

AU - Ciliberto, Andrea

AU - Gross, Fridolin

AU - Saurin, Adrian

N1 - Funding: Cancer Research UK (C47320/A21229 and C10988/A22566 to ATS)

PY - 2019/8/20

Y1 - 2019/8/20

N2 - PP1 and PP2A-B56 are major serine/threonine phosphatase families that achieve specificity by colocalizing with substrates. At the kinetochore, however, both phosphatases localize to an almost identical molecular space and yet they still manage to regulate unique pathways and processes. By switching or modulating the positions of PP1/PP2A-B56 at kinetochores, we show that their unique downstream effects are not due to either the identity of the phosphatase or its precise location. Instead, these phosphatases signal differently because their kinetochore recruitment can be either inhibited (PP1) or enhanced (PP2A) by phosphorylation inputs. Mathematical modeling explains how these inverse phospho-dependencies elicit unique forms of cross-regulation and feedback, which allows otherwise indistinguishable phosphatases to produce distinct network behaviors and control different mitotic processes. Furthermore, our genome-wide analysis suggests that these major phosphatase families may have evolved to respond to phosphorylation inputs in opposite ways because many other PP1 and PP2A-B56-binding motifs are also phospho-regulated.

AB - PP1 and PP2A-B56 are major serine/threonine phosphatase families that achieve specificity by colocalizing with substrates. At the kinetochore, however, both phosphatases localize to an almost identical molecular space and yet they still manage to regulate unique pathways and processes. By switching or modulating the positions of PP1/PP2A-B56 at kinetochores, we show that their unique downstream effects are not due to either the identity of the phosphatase or its precise location. Instead, these phosphatases signal differently because their kinetochore recruitment can be either inhibited (PP1) or enhanced (PP2A) by phosphorylation inputs. Mathematical modeling explains how these inverse phospho-dependencies elicit unique forms of cross-regulation and feedback, which allows otherwise indistinguishable phosphatases to produce distinct network behaviors and control different mitotic processes. Furthermore, our genome-wide analysis suggests that these major phosphatase families may have evolved to respond to phosphorylation inputs in opposite ways because many other PP1 and PP2A-B56-binding motifs are also phospho-regulated.

KW - Mitosis

KW - SAC

KW - SliM

KW - kinase

KW - kinetochore

KW - microtubule attachment

KW - phosphatase binding

KW - phosphorylation

KW - short linear motif

KW - spindle assembly checkpoint

UR - http://www.scopus.com/inward/record.url?scp=85070558564&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.07.067

DO - 10.1016/j.celrep.2019.07.067

M3 - Article

C2 - 31433993

VL - 28

SP - 2206-2219.e8

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 8

ER -