부산대학교 도서관

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. Synopsis: Distinct regulatory B‐subunits convey differing specificities on the essential phosphatase PP2A. Phosphoproteomic substrate identification of two PP2A holoenzymes reveal that B‐subunits directly affect dephosphorylation site preference of the common catalytic subunit. Phosphoproteomic strategies allow global substrate identification of PP2A‐B56 and PP2A‐B55 holoenzymes.Regulatory B‐subunits directly affect the dephosphorylation site preference of the PP2A catalytic subunit.Affinity and position of binding motifs modulate phosphorylation site selection of PP2A‐B56.PP2A‐B56 binding to the cancer target ADAM17 decreases growth factor signaling and tumor development in mice. [ABSTRACT FROM AUTHOR]