WNK1 controls endosomal trafficking through TRIM27-dependent regulation of actin assembly.
Proc Natl Acad Sci U S A
; 120(25): e2300310120, 2023 06 20.
Article
em En
| MEDLINE
| ID: mdl-37307465
ABSTRACT
The protein kinase WNK1 (with-no-lysine 1) influences trafficking of ion and small-molecule transporters and other membrane proteins as well as actin polymerization state. We investigated the possibility that actions of WNK1 on both processes are related. Strikingly, we identified the E3 ligase tripartite motif-containing 27 (TRIM27) as a binding partner for WNK1. TRIM27 is involved in fine tuning the WASH (Wiskott-Aldrich syndrome protein and SCAR homologue) regulatory complex which regulates endosomal actin polymerization. Knockdown of WNK1 reduced the formation of the complex between TRIM27 and its deubiquitinating enzyme USP7 (ubiquitin-specific protease 7), resulting in significantly diminished TRIM27 protein. Loss of WNK1 disrupted WASH ubiquitination and endosomal actin polymerization, which are necessary for endosomal trafficking. Sustained receptor tyrosine kinase (RTK) expression has long been recognized as a key oncogenic signal for the development and growth of human malignancies. Depletion of either WNK1 or TRIM27 significantly increased degradation of the epidermal growth factor receptor (EGFR) following ligand stimulation in breast and lung cancer cells. Like the EGFR, the RTK AXL was also affected similarly by WNK1 depletion but not by inhibition of WNK1 kinase activity. This study uncovers a mechanistic connection between WNK1 and the TRIM27-USP7 axis and extends our fundamental knowledge about the endocytic pathway regulating cell surface receptors.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Endossomos
/
Actinas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article