2ABG
sp|Q9Y2T4|2ABG_HUMAN
Uniprot
Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B gamma isoform OS=Homo sapiens GN=PPP2R2C PE=2 SV=4
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Sept. 5, 2019
Thomas Kruse , Isha Nasa , Hieu Nguyen , Arminja N. Kettenbach , Sebastian P. Gnosa , Dimitriya H. Garvanska , Jamin B. Hein , Jacob Samsøe-Petersen , Blanca Lopez-Mendez , Emil T. Hertz , Jeanette Schwarz , Hanna S. Pena , Denise Nikodemus , Marie Kveiborg , Jakob Nilsson
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 its tumor suppressor functions and the mechanisms of site-specific dephosphorylation. 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 binding motifs. Our screens identify phosphorylation sites in the cancer target ADAM17 that are regulated through a conserved B56 binding site. Dephosphorylation of ADAM17 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.