Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits
| Autor: | Jacob Samsøe-Petersen, Hanna Sofia Pena, Jeanette Schwarz, Jakob Nilsson, Blanca López-Méndez, Isha Nasa, Thomas Kruse, Jamin B Hein, Sebastian Gnosa, Marie Kveiborg, Hieu T Nguyen, Emil Peter Thrane Hertz, Denise Nikodemus, Dimitriya H Garvanska, Arminja N. Kettenbach |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
substrate specificity
tumor suppressor Protein subunit Phosphatase Amino Acid Motifs macromolecular substances Biology ADAM17 Protein environment and public health General Biochemistry Genetics and Molecular Biology Article Dephosphorylation 03 medical and health sciences Mice 0302 clinical medicine Holoenzymes Animals Humans Protein Phosphatase 2 Binding site Phosphorylation Molecular Biology 030304 developmental biology 0303 health sciences ADAM17 Binding Sites General Immunology and Microbiology Kinase General Neuroscience Cell Cycle Phosphoproteomics Post-translational Modifications Proteolysis & Proteomics phosphoproteomics Protein phosphatase 2 Articles 3. Good health Cell biology PP2A enzymes and coenzymes (carbohydrates) 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Kruse, T, Gnosa, S P, Nasa, I, Garvanska, D H, Hein, J B, Nguyen, H, Samsøe-Petersen, J, Lopez-Mendez, B, Hertz, E P T, Schwarz, J, Pena, H S, Nikodemus, D, Kveiborg, M, Kettenbach, A N & Nilsson, J 2020, ' Mechanisms of site-specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits ', EMBO Journal, vol. 39, e103695 . https://doi.org/10.15252/embj.2019103695 The EMBO Journal |
| Popis: | PP2A is an essential protein phosphatase that regulates most cellular processes through the formation of holoenzymes containing distinct regulatory B‐subunits. Only a limited number of PP2A‐regulated phosphorylation sites are known. This hampers our understanding of the mechanisms of site‐specific dephosphorylation and of its tumor suppressor functions. Here, we develop phosphoproteomic strategies for global substrate identification of PP2A‐B56 and PP2A‐B55 holoenzymes. Strikingly, we find that B‐subunits directly affect the dephosphorylation site preference of the PP2A catalytic subunit, resulting in unique patterns of kinase opposition. For PP2A‐B56, these patterns are further modulated by affinity and position of B56 binding motifs. Our screens identify phosphorylation sites in the cancer target ADAM17 that are regulated through a conserved B56 binding site. Binding of PP2A‐B56 to ADAM17 protease decreases growth factor signaling and tumor development in mice. This work provides a roadmap for the identification of phosphatase substrates and reveals unexpected mechanisms governing PP2A dephosphorylation site specificity and tumor suppressor function. Phosphoproteomics for global substrate identification of PP2A‐B56 and PP2A‐B55 holoenzymes reveal that B‐subunits directly affect dephosphorylation site preference of the common catalytic subunit. |
| Databáze: | OpenAIRE |
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