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PP2A-B' holoenzyme substrate recognition, regulation and role in cytokinesis
Univ Wisconsin Madison, McArdle Lab Canc Res, Dept Oncol, Sch Med & Publ Hlth, Madison, WI 53706 USA.; Univ Wisconsin Madison, Biophys Program, Madison, WI 53706 USA.; DuPont Ind Biosci, Genencor Div, 925 Page Mill Rd, Palo Alto, CA 94304 USA.
Univ Wisconsin Madison, McArdle Lab Canc Res, Dept Oncol, Sch Med & Publ Hlth, Madison, WI 53706 USA.; DuPont Ind Biosci, Genencor Div, 925 Page Mill Rd, Palo Alto, CA 94304 USA.
Univ Wisconsin Madison, McArdle Lab Canc Res, Dept Oncol, Sch Med & Publ Hlth, Madison, WI 53706 USA.; DuPont Ind Biosci, Genencor Div, 925 Page Mill Rd, Palo Alto, CA 94304 USA.; Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA USA.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. DuPont Ind Biosci, Genencor Div, 925 Page Mill Rd, Palo Alto, CA 94304 USA. (Ivarsson)
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2017 (English)In: Cell Discovery, ISSN 2056-5968, Vol. 3, article id 17027Article in journal (Refereed) Published
Abstract [en]

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'α-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.

Place, publisher, year, edition, pages
2017. Vol. 3, article id 17027
Keyword [en]
CIP2A, PP2A-B′ holoenzyme, SLiMs, centrosome, cytokinesis, midbody
National Category
Bioinformatics and Systems Biology
Identifiers
URN: urn:nbn:se:uu:diva-337721DOI: 10.1038/celldisc.2017.27ISI: 000414925200001PubMedID: 28884018OAI: oai:DiVA.org:uu-337721DiVA, id: diva2:1170607
Funder
Swedish Research Council, 2012-05092 2016-04965Carl Tryggers foundation , CTS15:226
Available from: 2018-01-04 Created: 2018-01-04 Last updated: 2018-02-12Bibliographically approved

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