TITLE

Tyrosine dephosphorylation is required for Bak activation in apoptosis

AUTHOR(S)
Fox, Joanna L; Ismail, Ferina; Azad, Abul; Ternette, Nicola; Leverrier, Sabrina; Edelmann, Mariola J; Kessler, Benedikt M; Leigh, Irene M; Jackson, Sarah; Storey, Alan
PUB. DATE
November 2010
SOURCE
EMBO Journal;11/17/2010, Vol. 29 Issue 22, p3853
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Activation of the cell-death mediator Bak commits a cell to mitochondrial apoptosis. The initial steps that govern Bak activation are poorly understood. To further clarify these pivotal events, we have investigated whether post-translational modifications of Bak impinge on its activation potential. In this study, we report that on apoptotic stimulation Bak undergoes dephosphorylation at tyrosine residue 108 (Y108), a critical event that is necessary but not sufficient for Bak activation, but is required both for early exposure of the occluded N-terminal domain and multimerisation. RNA interference (RNAi) screening identified non-receptor tyrosine phosphatases (PTPNs) required for Bak dephosphorylation and apoptotic induction through chemotherapeutic agents. Specifically, modulation of PTPN5 protein expression by siRNA and overexpression directly affected both Bak-Y108 phosphorylation and the initiation of Bak activation. We further show that MEK/ERK signalling directly affects Bak phosphorylation through inhibition of PTPN5 to promote cell survival. We propose a model of Bak activation in which the regulation of Bak dephosphorylation constitutes the initial step in the activation process, which reveals a previously unsuspected mechanism controlling the initiation of mitochondrial apoptosis.
ACCESSION #
55835608

 

Related Articles

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics