Journal article
PP2A-B′ holoenzyme substrate recognition, regulation and role in cytokinesis
Cell discovery, Vol.3(1), pp.17027-17027
08/08/2017
DOI: 10.1038/celldisc.2017.27
PMCID: PMC5586252
PMID: 28884018
Abstract
Protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase; it forms diverse heterotrimeric holoenzymes that counteract kinase actions. Using a peptidome that tiles the disordered regions of the human proteome, we identified proteins containing [LMFI]xx[ILV]xEx motifs that serve as interaction sites for B'-family PP2A regulatory subunits and holoenzymes. The B'-binding motifs have important roles in substrate recognition and in competitive inhibition of substrate binding. With more than 100 novel ligands identified, we confirmed that the recently identified LxxIxEx B' a-binding motifs serve as common binding sites for B' subunits with minor variations, and that S/T phosphorylation or D/E residues at positions 2, 7, 8 and 9 of the motifs reinforce interactions. Hundreds of proteins in the human proteome harbor intrinsic or phosphorylation-responsive B'-interaction motifs, and localize at distinct cellular organelles, such as midbody, predicting kinase-facilitated recruitment of PP2A-B' holoenzymes for tight spatiotemporal control of phosphorylation at mitosis and cytokinesis. Moroever, Polo-like kinase 1-mediated phosphorylation of Cyk4/RACGAP1, a centralspindlin component at the midbody, facilitates binding of both RhoA guanine nucleotide exchange factor (epithelial cell transforming sequence 2 (Ect2)) and PP2A-B' that in turn dephosphorylates Cyk4 and disrupts Ect2 binding. This feedback signaling loop precisely controls RhoA activation and specifies a restricted region for cleavage furrow ingression. Our results provide a framework for further investigation of diverse signaling circuits formed by PP2A-B' holoenzymes in various cellular processes.
Details
- Title: Subtitle
- PP2A-B′ holoenzyme substrate recognition, regulation and role in cytokinesis
- Creators
- Cheng-Guo Wu - University of Wisconsin–MadisonHui Chen - University of Wisconsin–MadisonFeng Guo - University of Wisconsin–MadisonVikash K. Yadav - Uppsala UniversitySean J. Mcilwain - University of Wisconsin–MadisonMichael Rowse - University of Wisconsin–MadisonAlka Choudhary - University of Wisconsin–MadisonZiqing Lin - Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, Human Prote Program, Madison, WI USAYitong Li - University of Wisconsin–MadisonTingjia Gu - University of Wisconsin–MadisonAiping Zheng - University of Wisconsin–MadisonQingge Xu - Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, Human Prote Program, Madison, WI USAWoojong Lee - University of Wisconsin–MadisonEduard Resch - Institute of MicroelectronicsBenjamin Johnson - University of Wisconsin–MadisonJenny Day - University of Wisconsin–MadisonYing Ge - Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, Human Prote Program, Madison, WI USAIrene M. Ong - University of Wisconsin–MadisonMark E. Burkard - University of Wisconsin–MadisonYlva Ivarsson - Uppsala UniversityYongna Xing - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Cell discovery, Vol.3(1), pp.17027-17027
- DOI
- 10.1038/celldisc.2017.27
- PMID
- 28884018
- PMCID
- PMC5586252
- NLM abbreviation
- Cell Discov
- ISSN
- 2056-5968
- eISSN
- 2056-5968
- Publisher
- Springer Nature
- Number of pages
- 19
- Grant note
- Department of Oncology, University of Wisconsin-Madison Wisconsin partnership funds S10OD018475 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA GM117058 / NIH R01 grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; Office of the Administrator (NIH) CTS15:226 / Carl Trygger foundation R01 GM096060-01 / NIH grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Landesoffensive zur Entwicklung Wissenschaftlich-okonomischer Exzellenz (LOEWE)-Center Translational Medicine and Pharmacology RSG-10-153-01-DMC / American Cancer Society Research Scholar Grant; American Cancer Society 2012-05092; 2016-04965 / Swedish research council; Swedish Research Council T32 CA157322 / NIH Tumor Development Postdoctoral Training Grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 08/08/2017
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984701256802771
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