Interrogating PP1 Activity in the MAPK Pathway with Optimized PP1-Disrupting Peptides.

Protein phosphatase-1 (PP1)-disrupting peptides (PDPs) are selective chemical modulators of PP1 that liberate the active PP1 catalytic subunit from regulatory proteins; thus allowing the dephosphorylation of nearby substrates. We have optimized the original cell-active PDP3 for enhanced stability, and obtained insights into the chemical requirements for stabilizing this 23-mer peptide for cellular applications. The optimized PDP-Nal was used to dissect the involvement of PP1 in the MAPK signaling cascade. Specifically, we have demonstrated that, in human osteosarcoma (U2OS) cells, phosphoMEK1/2 is a direct substrate of PP1, whereas dephosphorylation of phosphoERK1/2 is indirect and likely mediated through enhanced tyrosine phosphatase activity after PDP-mediated PP1 activation. Thus, as liberators of PP1 activity, PDPs represent a valuable tool for identifying the substrates of PP1 and understanding its role in diverse signaling cascades. © 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Citation

Yansong Wang, Bernhard Hoermann, Karolina Pavic, Malgorzata Trebacz, Pablo Rios, Maja Köhn. Interrogating PP1 Activity in the MAPK Pathway with Optimized PP1-Disrupting Peptides. Chembiochem : a European journal of chemical biology. 2019 Jan 02;20(1):66-71

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PMID: 30338897

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