The cleavage of Akt/protein kinase B by death receptor signaling is an important event in detachment-induced apoptosis.

Published

Journal Article

Epithelial cells undergo death receptor-dependent apoptosis when detached from matrix, a process termed anoikis. Activation of Akt/protein kinase B (PKB) by matrix attachment protects cells from anoikis. In this study, we establish a link between anoikis and Akt/PKB-mediated survival by demonstrating that Akt/PKB is cleaved by caspases in matrix-detached epithelial cells by a mechanism that involves death receptors. Reduced levels of Akt/PKB protein were observed in detached Madin-Darby canine kidney cells relative to cells attached to collagen. Equivalent levels of Akt/PKB, however, were detected in matrix-adherent and detached cells after inhibition of caspase activity or expression of an Akt/PKB mutant (D108+119A) that is resistant to caspase cleavage. The contribution of death domain-containing proteins to Akt/PKB cleavage was evidenced by the ability of dominant negative Fas-associated death domain to restore normal levels of Akt/PKB in matrix-detached cells. Importantly, expression of a cleavage-resistant Akt/PKB mutant protected matrix-detached cells from apoptosis. These studies suggest that members of the death receptor family promote the caspase-mediated cleavage of Akt/PKB and that this event contributes to anoikis.

Full Text

Duke Authors

Cited Authors

  • Bachelder, RE; Wendt, MA; Fujita, N; Tsuruo, T; Mercurio, AM

Published Date

  • September 14, 2001

Published In

Volume / Issue

  • 276 / 37

Start / End Page

  • 34702 - 34707

PubMed ID

  • 11463786

Pubmed Central ID

  • 11463786

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M102806200

Language

  • eng

Conference Location

  • United States