Dataset Information

Selective PP2A Enhancement through Biased Heterotrimer Stabilization.

ABSTRACT: Impairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to dephosphorylate hundreds of proteins is regulated by over 40 specificity-determining regulatory "B" subunits that compete for assembly and activation of heterogeneous PP2A heterotrimers. Here, we reveal how a small molecule, DT-061, specifically stabilizes the B56α-PP2A holoenzyme in a fully assembled, active state to dephosphorylate selective substrates, such as its well-known oncogenic target, c-Myc. Our 3.6 Å structure identifies molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme and highlight inherent mechanisms of PP2A complex assembly. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for therapeutic targeting, and aid in the development of phosphatase-based therapeutics tailored against disease specific phospho-protein targets.

SUBMITTER: Leonard D

PROVIDER: S-EPMC7243596 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Selective PP2A Enhancement through Biased Heterotrimer Stabilization.

Leonard Daniel D Huang Wei W Izadmehr Sudeh S O'Connor Caitlin M CM Wiredja Danica D DD Wang Zhizhi Z Zaware Nilesh N Chen Yinghua Y Schlatzer Daniela M DM Kiselar Janna J Vasireddi Nikhil N Schüchner Stefan S Perl Abbey L AL Galsky Matthew D MD Xu Wenqing W Brautigan David L DL Ogris Egon E Taylor Derek J DJ Narla Goutham G

Cell 20200420 3

Impairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to dephosphorylate hundreds of proteins is regulated by over 40 specificity-determining regulatory "B" subunits that compete for assembly and activation of heterogeneous PP2A heterotrimers. Here, we reveal how a small molecule, DT-061, specifically stabilizes the B56α-PP2A holoenzyme in a fully assembl ...[more]

PMID: 32315618

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Project description:Lung cancer is one of the most common cancer types in the world. Despite existing treatment strategies, overall patient survival remains low and new targeted therapies are required. Acidification of the tumor microenvironment drives the growth and metastasis of many cancers. Acid sensors such as acid-sensing ion channels (ASICs) may become promising targets for lung cancer therapy. Previously, we showed that inhibition of the ASIC1 channels by a recombinant analogue of mambalgin-2 from Dendroaspis polylepis controls oncogenic processes in leukemia, glioma, and melanoma cells. Here, we studied the effects and molecular targets of mambalgin-2 in lung adenocarcinoma A549 and Lewis cells, lung transformed WI-38 fibroblasts, and lung normal HLF fibroblasts. We found that mambalgin-2 inhibits the growth and migration of A549, metastatic Lewis P29 cells, and WI-38 cells, but not of normal fibroblasts. A549, Lewis, and WI-38 cells expressed different ASIC and ENaC subunits, while normal fibroblasts did not at all. Mambalgin-2 induced G2/M cell cycle arrest and apoptosis in lung adenocarcinoma cells. In line, acidification-evoked inward currents were observed only in A549 and WI-38 cells. Gene knockdown showed that the anti-proliferative and anti-migratory activity of mambalgin-2 is dependent on the expression of ASIC1a, α-ENaC, and γ-ENaC. Using affinity extraction and immunoprecipitation, mambalgin-2 targeting of ASIC1a/α-ENaC/γ-ENaC heteromeric channels in A549 cells was shown. Electrophysiology studies in Xenopus oocytes revealed that mambalgin-2 inhibits the ASIC1a/α-ENaC/γ-ENaC channels with higher efficacy than the ASIC1a channels, pointing on the heteromeric channels as a primary target of the toxin in cancer cells. Finally, bioinformatics analysis showed that the increased expression of ASIC1 and γ-ENaC correlates with a worse survival prognosis for patients with lung adenocarcinoma. Thus, the ASIC1a/α-ENaC/γ-ENaC heterotrimer can be considered a marker of cell oncogenicity and its targeting is promising for the design of new selective cancer therapeutics.

Dataset Information

Selective PP2A Enhancement through Biased Heterotrimer Stabilization.

Publications

Selective PP2A Enhancement through Biased Heterotrimer Stabilization.

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