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

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          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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          MultiNotch MS3 Enables Accurate, Sensitive, and Multiplexed Detection of Differential Expression across Cancer Cell Line Proteomes

          Graeme C McAlister, David Nusinow, Mark P. Jedrychowski … (2014)
          Multiplexed quantitation via isobaric chemical tags (e.g., tandem mass tags (TMT) and isobaric tags for relative and absolute quantitation (iTRAQ)) has the potential to revolutionize quantitative proteomics. However, until recently the utility of these tags was questionable due to reporter ion ratio distortion resulting from fragmentation of coisolated interfering species. These interfering signals can be negated through additional gas-phase manipulations (e.g., MS/MS/MS (MS3) and proton-transfer reactions (PTR)). These methods, however, have a significant sensitivity penalty. Using isolation waveforms with multiple frequency notches (i.e., synchronous precursor selection, SPS), we coisolated and cofragmented multiple MS2 fragment ions, thereby increasing the number of reporter ions in the MS3 spectrum 10-fold over the standard MS3 method (i.e., MultiNotch MS3). By increasing the reporter ion signals, this method improves the dynamic range of reporter ion quantitation, reduces reporter ion signal variance, and ultimately produces more high-quality quantitative measurements. To demonstrate utility, we analyzed biological triplicates of eight colon cancer cell lines using the MultiNotch MS3 method. Across all the replicates we quantified 8 378 proteins in union and 6 168 proteins in common. Taking into account that each of these quantified proteins contains eight distinct cell-line measurements, this data set encompasses 174 704 quantitative ratios each measured in triplicate across the biological replicates. Herein, we demonstrate that the MultiNotch MS3 method uniquely combines multiplexing capacity with quantitative sensitivity and accuracy, drastically increasing the informational value obtainable from proteomic experiments.
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            Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance.

            Andrew Burgess, Suzanne Vigneron, Estelle Brioudes … (2010)
            Here we show that the functional human ortholog of Greatwall protein kinase (Gwl) is the microtubule-associated serine/threonine kinase-like protein, MAST-L. This kinase promotes mitotic entry and maintenance in human cells by inhibiting protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates cyclin B-Cdc2 substrates. The complete depletion of Gwl by siRNA arrests human cells in G2. When the levels of this kinase are only partially depleted, however, cells enter into mitosis with multiple defects and fail to inactivate the spindle assembly checkpoint (SAC). The ability of cells to remain arrested in mitosis by the SAC appears to be directly proportional to the amount of Gwl remaining. Thus, when Gwl is only slightly reduced, cells arrest at prometaphase. More complete depletion correlates with the premature dephosphorylation of cyclin B-Cdc2 substrates, inactivation of the SAC, and subsequent exit from mitosis with severe cytokinesis defects. These phenotypes appear to be mediated by PP2A, as they could be rescued by either a double Gwl/PP2A knockdown or by the inhibition of this phosphatase with okadaic acid. These results suggest that the balance between cyclin B-Cdc2 and PP2A must be tightly regulated for correct mitotic entry and exit and that Gwl is crucial for mediating this regulation in somatic human cells.
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              From promiscuity to precision: protein phosphatases get a makeover.

              David M. Virshup, Shirish Shenolikar (2009)
              The control of biological events requires strict regulation using complex protein phosphorylation and dephosphorylation strategies. The bulk of serine-threonine dephosphorylations are catalyzed by a handful of phosphatase catalytic subunits, giving rise to the misconception that these phosphatases are promiscuous and unregulated enzymes in vivo. The reality is much more nuanced: PP1 and PP2A, the most abundant serine-threonine phosphatases, are, in fact, families of hundreds of protein serine/threonine phosphatases, assembled from a few catalytic subunits in combination with a highly diverse array of regulators. As recent publications illustrate, these regulatory subunits confer specificity, selectivity, localization, and regulation on these important enzymes.
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                Author and article information

                Contributors
                Isha Nasa: (View ORCID Profile)
                Lauren E. Cressey: (View ORCID Profile)
                Emil P. T. Hertz: (View ORCID Profile)
                Arminja N. Kettenbach: (View ORCID Profile)
                Journal
                Title: Science Signaling
                Abbreviated Title: Sci. Signal.
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Print): 1945-0877
                ISSN (Electronic): 1937-9145
                Publication date Created: September 08 2020
                Publication date Created: September 08 2020
                Publication date (Electronic): September 08 2020
                Publication date (Print): September 08 2020
                Volume: 13
                Issue: 648
                Page: eaba7823
                Affiliations
                [1 ]Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH 03755, USA.
                [2 ]Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center at Dartmouth, Lebanon, NH 03766, USA.
                [3 ]Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
                [4 ]Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth College, Lebanon, NH 03756, USA.
                [5 ]Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
                Article
                DOI: 10.1126/scisignal.aba7823
                PMC ID: 7579721
                PubMed ID: 32900880
                SO-VID: ad22e08a-82a1-4753-85c9-315b98a8b2d1
                Copyright © © 2020
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                https://www.sciencemag.org/about/science-licenses-journal-article-reuse

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