Identification of an antiapoptotic protein complex at death receptors View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2008-10-10

AUTHORS

M Sun, L Song, Y Li, T Zhou, R S Jope

ABSTRACT

Stimulation of death receptors activates the extrinsic apoptotic signaling pathway that leads to cell death. Although many steps of this apoptotic signaling cascade are known, few mechanisms that counterbalance the death signal have been described. We identified an antiapoptotic protein complex associated with death receptors that contains glycogen synthase kinase-3 (GSK3), DDX3 and cellular inhibitor of apoptosis protein-1 (cIAP-1). GSK3, DDX3 and cIAP-1 are associated in cells with each other and with death receptors. Blocking the actions of GSK3 or DDX3 potentiated caspase-3 activation induced by stimulation of four different death receptors in several types of cells. GSK3 restrained apoptotic signaling by inhibiting formation of the death-inducing signaling complex and caspase-8 activation. Stimulated death receptors surmount the antiapoptotic complex by causing GSK3 inactivation and cleavage of DDX3 and cIAP-1 to enable progression of the apoptotic signaling cascade, but the antiapoptotic complex remains functional in cancer cells resistant to death receptor stimulation, a resistance that is overcome by GSK3 inhibitors. Thus, an antiapoptotic complex of GSK3, DDX3 and cIAP-1 caps death receptors, providing a checkpoint to counterbalance apoptotic signaling. More... »

PAGES

1887-1900

Journal

TITLE

Cell Death & Differentiation

ISSUE

12

VOLUME

15

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/cdd.2008.124

DOI

http://dx.doi.org/10.1038/cdd.2008.124

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1001921276

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/18846110


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