Journal
CELL DISCOVERY
Volume 3, Issue -, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/celldisc.2017.27
Keywords
PP2A-B ' holoenzyme; CIP2A; cytokinesis; midbody; centrosome; SLiMs
Categories
Funding
- NIH grant [R01 GM096060-01]
- American Cancer Society Research Scholar Grant [RSG-10-153-01-DMC]
- NIH Tumor Development Postdoctoral Training Grant [T32 CA157322]
- Swedish research council [2012-05092, 2016-04965]
- Carl Trygger foundation [CTS15:226]
- Department of Oncology, University of Wisconsin-Madison
- Landesoffensive zur Entwicklung Wissenschaftlich-okonomischer Exzellenz (LOEWE)-Center Translational Medicine and Pharmacology
- Wisconsin partnership funds
- NIH [S10OD018475]
- NIH R01 grant [GM117058]
- Swedish Research Council [2012-05092] Funding Source: Swedish Research Council
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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.
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