cGMP-dependent protein kinase Iß regulates breast cancer cell migration and invasion via interaction with the actin/myosin-associated protein caldesmon.
J Cell Sci
; 126(Pt 7): 1626-36, 2013 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-23418348
ABSTRACT
The two isoforms of type I cGMP-dependent protein kinase (PKGIα and PKGIß) differ in their first â¼100 amino acids, giving each isoform unique dimerization and autoinhibitory domains. The dimerization domains form coiled-coil structures and serve as platforms for isoform-specific protein-protein interactions. Using the PKGIß dimerization domain as an affinity probe in a proteomic screen, we identified the actin/myosin-associated protein caldesmon (CaD) as a PKGIß-specific binding protein. PKGIß phosphorylated human CaD on serine 12 in vitro and in intact cells. Phosphorylation on serine 12 or mutation of serine 12 to glutamic acid (S12E) reduced the interaction between CaD and myosin IIA. Because CaD inhibits myosin ATPase activity and regulates cell motility, we examined the effects of PKGIß and CaD on cell migration and invasion. Inhibition of the NO/cGMP/PKG pathway reduced migration and invasion of human breast cancer cells, whereas PKG activation enhanced their motility and invasion. siRNA-mediated knockdown of endogenous CaD had pro-migratory and pro-invasive effects in human breast cancer cells. Reconstituting cells with wild-type CaD slowed migration and invasion; however, CaD containing a phospho-mimetic S12E mutation failed to reverse the pro-migratory and pro-invasive activity of CaD depletion. Our data suggest that PKGIß enhances breast cancer cell motility and invasive capacity, at least in part, by phosphorylating CaD. These findings identify a pro-migratory and pro-invasive function for PKGIß in human breast cancer cells, suggesting that PKGIß is a potential target for breast cancer treatment.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação a Calmodulina
/
Actinas
/
Miosinas
/
Proteína Quinase Dependente de GMP Cíclico Tipo I
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Female
/
Humans
Idioma:
En
Revista:
J Cell Sci
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos