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Mechanisms of site‐specific dephosphorylation and kinase opposition imposed by PP2A regulatory subunits
Author(s) -
Kruse Thomas,
Gnosa Sebastian Peter,
Nasa Isha,
Garvanska Dimitriya Hristoforova,
Hein Jamin B,
Nguyen Hieu,
SamsøePetersen Jacob,
LopezMendez Blanca,
Hertz Emil Peter Thrane,
Schwarz Jeanette,
Pena Hanna Sofia,
Nikodemus Denise,
Kveiborg Marie,
Kettenbach Arminja N,
Nilsson Jakob
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019103695
Subject(s) - biology , dephosphorylation , protein phosphatase 2 , phosphorylation , protein subunit , microbiology and biotechnology , kinase , genetics , phosphatase , gene
Abstract 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.