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Titolo
Connexin43 recruits PTEN and Csk to inhibit c-Src activity in glioma cells and astrocytes
Autor(es)
Soggetto
Connexin
Src
Glia
CNS
Gap junctions
Clasificación UNESCO
2302 Bioquímica
2490 Neurociencias
Fecha de publicación
2016
Citación
González-Sánchez, A., Jaraíz-Rodríguez, M., Domínguez-Prieto, M., Herrero-González, S., Medina, J. M., & Tabernero, A. (2016). Connexin43 recruits PTEN and Csk to inhibit c-Src activity in glioma cells and astrocytes. Oncotarget, 7(31), 49819.
Resumen
[EN] Connexin43 (Cx43), the major protein forming gap junctions in astrocytes,
is reduced in high-grade gliomas, where its ectopic expression exerts important
effects, including the inhibition of the proto-oncogene tyrosine-protein kinase Src
(c-Src). In this work we aimed to investigate the mechanism responsible for this
effect. The inhibition of c-Src requires phosphorylation at tyrosine 527 mediated
by C-terminal Src kinase (Csk) and dephosphorylation at tyrosine 416 mediated by
phosphatases, such as phosphatase and tensin homolog (PTEN). Our results showed
that the antiproliferative effect of Cx43 is reduced when Csk and PTEN are silenced
in glioma cells, suggesting the involvement of both enzymes. Confocal microscopy
and immunoprecipitation assays confirmed that Cx43, in addition to c-Src, binds to
PTEN and Csk in glioma cells transfected with Cx43 and in astrocytes. Pull-down
assays showed that region 266–283 in Cx43 is sufficient to recruit c-Src, PTEN and
Csk and to inhibit the oncogenic activity of c-Src. As a result of c-Src inhibition, PTEN
was increased with subsequent inactivation of Akt and reduction of proliferation of
human glioblastoma stem cells. We conclude that the recruitment of Csk and PTEN
to the region between residues 266 and 283 within the C-terminus of Cx43 leads to
c-Src inhibition.
URI
ISSN
1949-2553
DOI
10.18632/oncotarget.10454
Versión del editor
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