Discovery - University of Dundee - Online Publications

Library & Learning Centre

Tyrosine dephosphorylation is required for Bak activation in apoptosis

Tyrosine dephosphorylation is required for Bak activation in apoptosis

Research output: Contribution to journalArticle

View graph of relations

Authors

  • Joanna L. Fox
  • Ferina Ismail
  • Abul Azad
  • Nicola Ternette
  • Sabrina Leverrier
  • Mariola J. Edelmann
  • Benedikt M. Kessler
  • Irene M. Leigh
  • Sarah Jackson
  • Alan Storey

Research units

Info

Original languageEnglish
Pages3853-3868
Number of pages16
JournalEMBO Journal
Journal publication date17 Nov 2010
Volume29
Issue22
DOIs
StatePublished

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 multi-merisation. 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.

Documents

Library & Learning Centre

Contact | Accessibility | Policy