Journal
EMBO JOURNAL
Volume 39, Issue 13, Pages -Publisher
WILEY
DOI: 10.15252/embj.2019103695
Keywords
ADAM17; phosphoproteomics; PP2A; substrate specificity; tumor suppressor
Categories
Funding
- Danish Cancer Society [R167-A10951-17-S2, R146-A9211-16-S2]
- Independent Research Fund Denmark [DFF 8021-00101B, DFF 7016 00086]
- Novo Nordisk Foundation [NNF18OC0053124]
- NIH/NIGMS [R35GM119455, P20GM113132]
- NIH [S10-OD016212]
- European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant [798716]
- [NNF14CC0001]
- Marie Curie Actions (MSCA) [798716] Funding Source: Marie Curie Actions (MSCA)
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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.
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