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

Richard J Smith, Marilia H Cordeiro, Norman E Davey, Giulia Vallardi, Andrea Ciliberto, Fridolin Gross, View ORCID ProfileAdrian T Saurin
doi: https://doi.org/10.1101/610808
Richard J Smith
1Division of Cellular Medicine, School of Medicine, University of Dundee. DD1 9SY
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Marilia H Cordeiro
1Division of Cellular Medicine, School of Medicine, University of Dundee. DD1 9SY
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Norman E Davey
2Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
3Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
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Giulia Vallardi
1Division of Cellular Medicine, School of Medicine, University of Dundee. DD1 9SY
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Andrea Ciliberto
4Istituto Firc di Oncologia Molecolare, IFOM, Milano, Italy
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Fridolin Gross
4Istituto Firc di Oncologia Molecolare, IFOM, Milano, Italy
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Adrian T Saurin
1Division of Cellular Medicine, School of Medicine, University of Dundee. DD1 9SY
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  • ORCID record for Adrian T Saurin
  • For correspondence: a.saurin@dundee.ac.uk
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Abstract

PP1 and PP2A-B56 are major serine/threonine phosphatase families that achieve specificity by colocalising with substrates. At the kinetochore, however, both phosphatases localise 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 modelling explains how these inverse phospho-dependencies elicit unique forms of cross-regulation and feedback, which allows otherwise indistinguishable phosphatases to produce distinct network behaviours and control different mitotic processes. Therefore, the kinetochore uses PP1 and PP2A-B56 because their binding motifs respond to kinase inputs in opposite ways. Genome-wide motif analysis suggests that many other pathways also select for these same key features, implying that these similar catalytic enzymes may have diverged during evolution to allow opposite modes of phospho-regulation.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 05, 2019.
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PP1 and PP2A use opposite phospho-dependencies to control distinct processes at the kinetochore
Richard J Smith, Marilia H Cordeiro, Norman E Davey, Giulia Vallardi, Andrea Ciliberto, Fridolin Gross, Adrian T Saurin
bioRxiv 610808; doi: https://doi.org/10.1101/610808
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PP1 and PP2A use opposite phospho-dependencies to control distinct processes at the kinetochore
Richard J Smith, Marilia H Cordeiro, Norman E Davey, Giulia Vallardi, Andrea Ciliberto, Fridolin Gross, Adrian T Saurin
bioRxiv 610808; doi: https://doi.org/10.1101/610808

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