| First Author | Huang Q | Year | 2020 |
| Journal | EMBO J | Volume | 39 |
| Issue | 14 | Pages | e104410 |
| PubMed ID | 32511789 | Mgi Jnum | J:293949 |
| Mgi Id | MGI:6452519 | Doi | 10.15252/embj.2020104410 |
| Citation | Huang Q, et al. (2020) MDMX inhibits casein kinase 1alpha activity and stimulates Wnt signaling. EMBO J 39(14):e104410 |
| abstractText | Casein kinase 1 alpha (CK1alpha) is a serine/threonine kinase with numerous functions, including regulating the Wnt/beta-catenin and p53 pathways. CK1alpha 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 CK1alpha, suggesting that MDMX may in turn regulate CK1alpha function. We present evidence that MDMX is a potent competitive inhibitor of CK1alpha kinase activity (Ki = 8 nM). Depletion of MDMX increases CK1alpha activity and beta-catenin S45 phosphorylation, whereas ectopic MDMX expression inhibits CK1alpha activity and beta-catenin phosphorylation. The MDMX acidic domain and zinc finger are necessary and sufficient for binding and inhibition of CK1alpha. P53 binding to MDMX disrupts an intramolecular auto-regulatory interaction and enhances its ability to inhibit CK1alpha. P53-null mice expressing the MDMX(W) (200S/W201G) mutant, defective in CK1alpha binding, exhibit reduced Wnt/beta-catenin target gene expression and delayed tumor development. Therefore, MDMX is a physiological inhibitor of CK1alpha and has a role in modulating cellular response to Wnt signaling. The MDMX-CK1alpha interaction may account for certain p53-independent functions of MDMX. |
