RT Journal Article
SR Electronic
T1 PP1 and PP2A use opposite phospho-dependencies to control distinct processes at the kinetochore
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 610808
DO 10.1101/610808
A1 Richard J Smith
A1 Marilia H Cordeiro
A1 Norman E Davey
A1 Giulia Vallardi
A1 Andrea Ciliberto
A1 Fridolin Gross
A1 Adrian T Saurin
YR 2019
UL http://biorxiv.org/content/early/2019/05/05/610808.abstract
AB 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.