Quantitative kinase and phosphatase profiling reveal that CDK1 phosphorylates PP2Ac to promote mitotic entry.
Isha NasaLauren E CresseyThomas KruseEmil P T HertzJiang GuiLee M GravesJakob NilssonArminja N KettenbachPublished in: Science signaling (2020)
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.
Keyphrases
- cell cycle
- protein kinase
- cell proliferation
- mass spectrometry
- induced apoptosis
- cell cycle arrest
- transcription factor
- single cell
- high resolution
- gene expression
- endoplasmic reticulum stress
- multidrug resistant
- cell death
- oxidative stress
- dna methylation
- genome wide
- crystal structure
- atomic force microscopy
- resting state
- ms ms
- functional connectivity