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.
