The phosphorylation of the Smad2/3 linker region by nemo-like kinase regulates TGF-ß signaling.
J Biol Chem
; 296: 100512, 2021.
Article
em En
| MEDLINE
| ID: mdl-33676893
ABSTRACT
Smad2 and Smad3 (Smad2/3) are structurally similar proteins that primarily mediate the transforming growth factor-ß (TGF-ß) signaling responsible for driving cell proliferation, differentiation, and migration. The dynamics of the Smad2/3 phosphorylation provide the key mechanism for regulating the TGF-ß signaling pathway, but the details surrounding this phosphorylation remain unclear. Here, using in vitro kinase assay coupled with mass spectrometry, we identified for the first time that nemo-like kinase (NLK) regulates TGF-ß signaling via modulation of Smad2/3 phosphorylation in the linker region. TGF-ß-mediated transcriptional and cellular responses are suppressed by NLK overexpression, whereas NLK depletion exerts opposite effects. Specifically, we discovered that NLK associates with Smad3 and phosphorylates the designated serine residues located in the linker region of Smad2 and Smad3, which inhibits phosphorylation at the C terminus, thereby decreasing the duration of TGF-ß signaling. Overall, this work demonstrates that phosphorylation on the linker region of Smad2/3 by NLK counteracts the canonical phosphorylation in response to TGF-ß signals, thus providing new insight into the mechanisms governing TGF-ß signaling transduction.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta
/
Proteínas Serina-Treonina Quinases
/
Proteína Smad2
/
Proteína Smad3
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
China