MDMX inhibits casein kinase 1α activity and stimulates Wnt signaling

Abstract

Casein kinase 1 alpha (CK1a) is a serine/threonine kinase with numerous functions, including regulating the Wnt/b-catenin and p53 pathways. CK1a 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 CK1a, suggesting that MDMX may in turn regulate CK1a function. We present evidence that MDMX is a potent competitive inhibitor of CK1a kinase activity (K i = 8 nM). Depletion of MDMX increases CK1a activity and b-catenin S45 phosphorylation, whereas ectopic MDMX expression inhibits CK1a activity and b-catenin phosphorylation. The MDMX acidic domain and zinc finger are necessary and sufficient for binding and inhibition of CK1a. P53 binding to MDMX disrupts an intramolecular auto-regulatory interaction and enhances its ability to inhibit CK1a. P53-null mice expressing the MDMX W200S/W201G mutant, defective in CK1a binding, exhibit reduced Wnt/b-catenin target gene expression and delayed tumor development. Therefore, MDMX is a physiological inhibitor of CK1a and has a role in modulating cellular response to Wnt signaling. The MDMX-CK1a interaction may account for certain p53-independent functions of MDMX.