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PP2A-B′ holoenzyme substrate recognition, regulation and role in cytokinesis

: Wu, C.-G.; Chen, H.; Guo, F.; Yadav, V.K.; McIlwain, S.J.; Rowse, M.; Choudhary, A.; Lin, Z.; Li, Y.; Gu, T.; Zheng, A.; Xu, Q.; Lee, W.; Resch, E.; Johnson, B.; Day, J.; Ge, Y.; Ong, I.M.; Burkard, M.E.; Ivarsson, Y.; Xing, Y.

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Cell discovery 3 (2017), Art. 17027, 19 S.
ISSN: 2056-5968
Zeitschriftenaufsatz, Elektronische Publikation
Fraunhofer IME ()

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.