{"doi":"10.1101/2020.10.05.326793","title":"Bistable, biphasic regulation of PP2A-B55 accounts for the dynamics of mitotic substrate phosphorylation","abstract":"Summary The phosphorylation of mitotic proteins is bistable, which contributes to the decisiveness of the transitions into and out of M phase. The bistability in substrate phosphorylation has been attributed to bistability in the activation of the cyclin-dependent kinase Cdk1. However, more recently it has been suggested that bistability also arises from positive feedback in the regulation of the Cdk1-counteracting phosphatase, PP2A-B55. Here, we demonstrate biochemically using Xenopus laevis egg extracts that the Cdk1-counteracting phosphatase PP2A-B55 functions as a bistable switch, even when the bistability of Cdk1 activation is suppressed. In addition, Cdk1 regulates PP2A-B55 in a biphasic manner; low concentrations of Cdk1 activate PP2A-B55 and high concentrations inactivate it. As a consequence of this incoherent feedforward regulation, PP2A-B55 activity rises concurrently with Cdk1 activity during interphase and suppresses substrate phosphorylation. PP2A-B55 activity is then sharply downregulated at the onset of mitosis. During mitotic exit Cdk1 activity initially falls with no obvious change in substrate phosphorylation; dephosphorylation then commences once PP2A-B55 spikes in activity. These findings suggest that changes in Cdk1 activity are permissive for mitotic entry and exit, but the changes in PP2A-B55 activity are the ultimate trigger.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":124087,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9421,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":459951,"name":"Lendert Gelens","orcid":"0000-0001-7290-9561","position":1,"is_corresponding":false},{"id":459952,"name":"James E. Ferrell","orcid":"0000-0003-4767-3926","position":2,"is_corresponding":false},{"id":459950,"name":"Julia Kamenz","orcid":"0000-0001-9673-5404","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-18T23:15:07.789881Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}