Axl phosphorylates Elmo scaffold proteins to promote Rac activation and cell invasion.
Mol Cell Biol
; 35(1): 76-87, 2015 Jan.
Article
en En
| MEDLINE
| ID: mdl-25332238
ABSTRACT
The receptor tyrosine kinase Axl contributes to cell migration and invasion. Expression of Axl correlates with metastatic progression in cancer patients, yet the specific signaling events promoting invasion downstream of Axl are poorly defined. Herein, we report Elmo scaffolds to be direct substrates and binding partners of Axl. Elmo proteins are established to interact with Dock family guanine nucleotide exchange factors to control Rac-mediated cytoskeletal dynamics. Proteomics and mutagenesis studies reveal that Axl phosphorylates Elmo1/2 on a conserved carboxyl-terminal tyrosine residue. Upon Gas6-dependent activation of Axl, endogenous Elmo2 becomes phosphorylated on Tyr-713 and enters into a physical complex with Axl in breast cancer cells. Interfering with Elmo2 expression prevented Gas6-induced Rac1 activation in breast cancer cells. Similarly to blocking of Axl, Elmo2 knockdown or pharmacological inhibition of Dock1 abolishes breast cancer cell invasion. Interestingly, Axl or Elmo2 knockdown diminishes breast cancer cell proliferation. Rescue of Elmo2 knockdown cells with the wild-type protein but not with Elmo2 harboring Tyr-713-Phe mutations restores cell invasion and cell proliferation. These results define a new mechanism by which Axl promotes cell proliferation and invasion and identifies inhibition of the Elmo-Dock pathway as a potential therapeutic target to stop Axl-induced metastases.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
/
Proteínas Proto-Oncogénicas
/
Proteínas Tirosina Quinasas Receptoras
/
Proteínas de Unión al GTP rac
/
Proteínas del Citoesqueleto
/
Proteínas Adaptadoras Transductoras de Señales
Tipo de estudio:
Prognostic_studies
Límite:
Female
/
Humans
Idioma:
En
Revista:
Mol Cell Biol
Año:
2015
Tipo del documento:
Article
País de afiliación:
Canadá