MDMX inhibits casein kinase 1α activity and stimulates Wnt signaling.
EMBO J
; 39(14): e104410, 2020 07 15.
Article
em En
| MEDLINE
| ID: mdl-32511789
ABSTRACT
Casein kinase 1 alpha (CK1α) is a serine/threonine kinase with numerous functions, including regulating the Wnt/ß-catenin and p53 pathways. CK1α 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 CK1α, suggesting that MDMX may in turn regulate CK1α function. We present evidence that MDMX is a potent competitive inhibitor of CK1α kinase activity (Ki = 8 nM). Depletion of MDMX increases CK1α activity and ß-catenin S45 phosphorylation, whereas ectopic MDMX expression inhibits CK1α activity and ß-catenin phosphorylation. The MDMX acidic domain and zinc finger are necessary and sufficient for binding and inhibition of CK1α. P53 binding to MDMX disrupts an intramolecular auto-regulatory interaction and enhances its ability to inhibit CK1α. P53-null mice expressing the MDMXW200S/W201G mutant, defective in CK1α binding, exhibit reduced Wnt/ß-catenin target gene expression and delayed tumor development. Therefore, MDMX is a physiological inhibitor of CK1α and has a role in modulating cellular response to Wnt signaling. The MDMX-CK1α interaction may account for certain p53-independent functions of MDMX.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas
/
Proteínas de Ciclo Celular
/
Caseína Quinase Ialfa
/
Via de Sinalização Wnt
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article