Research ArticleMitosis

Quantitative kinase and phosphatase profiling reveal that CDK1 phosphorylates PP2Ac to promote mitotic entry

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Science Signaling  08 Sep 2020:
Vol. 13, Issue 648, eaba7823
DOI: 10.1126/scisignal.aba7823

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A kinase-phosphatase relationship in mitosis

Mitosis generally involves a wave of phosphorylation at entry and dephosphorylation at exit. More is understood about the role of kinases than that of phosphatases in this dynamic. Nasa et al. developed an integrated approach to study the interaction dynamics of the kinome-phosphatome in mitotic cells. This approach revealed that the formation of the PP2Ac-B55 phosphatase was critical for mitotic exit and maintenance of interphase. It also revealed that the phosphorylation mediated by the kinase CDK1 directly and indirectly dissociated the subunits of the phosphatase, thereby enabling mitotic entry. The findings refine our understanding of regulatory phosphorylation in mitosis and present a method with which to further examine kinase-phosphatase relationships in other contexts.

Abstract

The reciprocal regulation of phosphoprotein phosphatases (PPPs) by protein kinases is essential to cell cycle progression and control, particularly during mitosis for which the role of kinases has been extensively studied. PPPs perform much of the serine/threonine dephosphorylation in eukaryotic cells and achieve substrate selectivity and specificity through the interaction of distinct regulatory subunits with conserved catalytic subunits in holoenzyme complexes. Using a mass spectrometry–based chemical proteomics approach to enrich, identify, and quantify endogenous PPP holoenzyme complexes combined with kinase profiling, we investigated the phosphorylation-dependent regulation of PPP holoenzymes in mitotic cells. We found that cyclin-dependent kinase 1 (CDK1) phosphorylated a threonine residue on the catalytic subunit of the phosphatase PP2A, which disrupted its holoenzyme formation with the regulatory subunit B55. The consequent decrease in the dephosphorylation of PP2A-B55 substrates promoted mitotic entry. This direct phosphorylation by CDK1 was in addition to a previously reported indirect mechanism, thus adding a layer to the interaction between CDK1 and PP2A in regulating mitotic entry.

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