Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling.
Elife
; 62017 04 22.
Article
em En
| MEDLINE
| ID: mdl-28432785
ABSTRACT
Proteolytic cleavage and release from the cell surface of membrane-tethered ligands is an important mechanism of regulating intercellular signalling. TACE is a major shedding protease, responsible for the liberation of the inflammatory cytokine TNFα and ligands of the epidermal growth factor receptor. iRhoms, catalytically inactive members of the rhomboid-like superfamily, have been shown to control the ER-to-Golgi transport and maturation of TACE. Here, we reveal that iRhom2 remains associated with TACE throughout the secretory pathway, and is stabilised at the cell surface by this interaction. At the plasma membrane, ERK1/2-mediated phosphorylation and 14-3-3 protein binding of the cytoplasmic amino-terminus of iRhom2 alter its interaction with mature TACE, thereby licensing its proteolytic activity. We show that this molecular mechanism is responsible for triggering inflammatory responses in primary mouse macrophages. Overall, iRhom2 binds to TACE throughout its lifecycle, implying that iRhom2 is a primary regulator of stimulated cytokine and growth factor signalling.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Proteínas de Transporte
/
Membrana Celular
/
Processamento de Proteína Pós-Traducional
/
Proteína ADAM17
Limite:
Animals
Idioma:
En
Revista:
Elife
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Reino Unido