PP1 and PP2A Use Opposite Phospho-dependencies to Control Distinct Processes at the Kinetochore

Cell Rep. 2019 Aug 20;28(8):2206-2219.e8. doi: 10.1016/j.celrep.2019.07.067.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • HeLa Cells
  • Humans
  • Kinetochores / metabolism*
  • Microtubule-Associated Proteins / metabolism
  • Models, Biological
  • Phenotype
  • Phosphorylation
  • Protein Phosphatase 2 / chemistry
  • Protein Phosphatase 2 / metabolism*
  • Receptors, Neuropeptide Y / chemistry
  • Receptors, Neuropeptide Y / metabolism*
  • Signal Transduction


  • Knl1 protein, human
  • Microtubule-Associated Proteins
  • Receptors, Neuropeptide Y
  • neuropeptide Y4 receptor
  • PP2A-B56alpha protein, human
  • Protein Phosphatase 2