MDMX inhibits casein kinase 1? activity and stimulates Wnt signaling.

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 MDMXW 200S/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.
Mesh Terms:
A549 Cells, Animals, Casein Kinase Ialpha, Cell Cycle Proteins, HEK293 Cells, Humans, Mice, Mice, Knockout, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Wnt Signaling Pathway, beta Catenin
EMBO J
Date: Dec. 15, 2019
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