Identification of a CIP4 PKA phosphorylation site involved in the regulation of cancer cell invasiveness and metastasis.
Cancer Lett
; 461: 65-77, 2019 Oct 01.
Article
en En
| MEDLINE
| ID: mdl-31319138
ABSTRACT
CDC42 interacting protein 4 (CIP4) is a CDC42 effector that coordinates membrane deformation and actin polymerization. The correlation of CIP4 overexpression with metastatic capacity has been characterized in several types of cancer. However, little information exists on how CIP4 function is regulated. CIP4 interacts with A-kinase (PKA) anchoring protein 350 (AKAP350) and CIP4 is also a PKA substrate. Here, we identified CIP4 T225 as the major CIP4 PKA phosphorylation site. In vitro and in vivo experiments using hepatocellular carcinoma (HCC) and breast cancer cells showed that expression of a CIP4(T225E) phosphomimetic mutant increased cancer cell metastatic capacity and that, conversely, expression of a CIP4(T225A) non-phosphorylatable mutant reduced invasive properties. PKA inhibition decreased to CIP4(T225A) cell-levels control but not CIP4(T225E) cell migratory and invasive efficiency. Concomitantly, our studies indicate that CIP4 T225 phosphorylation promotes the formation of functional invadopodia and enhances CIP4 localization at these structures. Our findings further provide mechanistic data indicating that CIP4 T225 phosphorylation facilitates CIP4 interaction with CDC42. Altogether this study identifies a signaling pathway that involves CIP4 phosphorylation by PKA during the acquisition of a metastatic phenotype in cancer cells.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
/
Antígenos de Histocompatibilidad Menor
/
Proteínas Quinasas Dependientes de AMP Cíclico
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Carcinoma Hepatocelular
/
Neoplasias Hepáticas
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Neoplasias Pulmonares
/
Proteínas Asociadas a Microtúbulos
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
Cancer Lett
Año:
2019
Tipo del documento:
Article
País de afiliación:
Argentina
Pais de publicación:
IE
/
IRELAND
/
IRLANDA