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MDMX inhibits Casein Kinase 1? activity and stimulates Wnt signaling

ABSTRACT: Casein kinase 1 alpha (CK1?) is a serine/threonine kinase with numerous functions, including regulating the Wnt/?-catenin and p53 pathways. CK1? has a well-established role in inhibiting the p53 tumor suppressor by binding to MDMX and stimulating MDMX-p53 interaction. MDMX purified from cells contains near-stoichiometric amounts of CK1?, suggesting that MDMX may in turn regulate CK1? function. We present evidence that MDMX is a potent competitive inhibitor of CK1? kinase activity (Ki=8 nM). Depletion of MDMX increases CK1? activity and ?-catenin S45 phosphorylation, whereas ectopic MDMX expression inhibits CK1? activity and ?-catenin phosphorylation. The MDMX acidic domain and zinc finger are necessary and sufficient for binding and inhibition of CK1?. P53 binding to MDMX disrupts an intramolecular auto-regulatory interaction and enhances its ability to inhibit CK1?. P53-null mice expressing the MDMXW200S/W201G mutant, defective in CK1? binding, exhibit reduced Wnt/?-catenin target gene expression and delayed tumor development. Therefore, MDMX is a physiological inhibitor of CK1? and has a role in modulating cellular response to Wnt signaling. The MDMX-CK1? interaction may account for certain p53-independent functions of MDMX.

SUBMITTER: Prof. Jiandong Chen

PROVIDER: S-SCDT-EMBOJ-2020-104410 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:The cellular and organismal phenotypic response to a small-molecule kinase inhibitor is defined collectively by the inhibitor's targets and their functions. The selectivity of small-molecule kinase inhibitors is commonly determined in vitro, using purified kinases and substrates. Recently, competitive chemical proteomics has emerged as a complementary, unbiased, cell-based methodology to define the target landscape of kinase inhibitors. Here, we evaluated and optimized a competitive multiplexed inhibitor bead mass spectrometry (MIB/MS) platform using cell lysates, live cells, and treated mice. Several clinically active kinase inhibitors were profiled, including trametinib, BMS-777607, dasatinib, abemaciclib, and palbociclib. MIB/MS competition analyses of the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors abemaciclib and palbociclib revealed overlapping and unique kinase targets. Competitive MIB/MS analysis of abemaciclib revealed 83 target kinases, and dose-response MIB/MS profiling revealed glycogen synthase kinase 3 alpha and beta (GSK3? and ?) and Ca2+/calmodulin-dependent protein kinase II delta and gamma (CAMKII? and ?) as the most potently inhibited. Cell-based and in vitro kinase assays show that in contrast to palbociclib, abemaciclib directly inhibits GSK3?/? and CAMKII?/? kinase activity at low nanomolar concentrations. GSK3? phosphorylates ?-catenin to suppress WNT signaling, while abemaciclib (but not palbociclib or ribociclib) potently activates ?-catenin-dependent WNT signaling. These data illustrate the power of competitive chemical proteomics to define kinase target specificities for kinase inhibitors, thus informing clinical efficacy, dose-limiting toxicities, and drug-repurposing efforts.Implications: This study uses a rapid and quantitative proteomics approach to define inhibitor-target data for commonly administered therapeutics and provides a cell-based alternative to in vitro kinome profiling. Mol Cancer Res; 16(2); 333-44. ©2017 AACR.

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MDMX inhibits Casein Kinase 1? activity and stimulates Wnt signaling

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