Tyrosine dephosphorylation is required for Bak activation in apoptosis

TY - JOUR

T1 - Tyrosine dephosphorylation is required for Bak activation in apoptosis

A1 - Fox,Joanna L.

A1 - Ismail,Ferina

A1 - Azad,Abul

A1 - Ternette,Nicola

A1 - Leverrier,Sabrina

A1 - Edelmann,Mariola J.

A1 - Kessler,Benedikt M.

A1 - Leigh,Irene M.

A1 - Jackson,Sarah

A1 - Storey,Alan

AU - Fox,Joanna L.

AU - Ismail,Ferina

AU - Azad,Abul

AU - Ternette,Nicola

AU - Leverrier,Sabrina

AU - Edelmann,Mariola J.

AU - Kessler,Benedikt M.

AU - Leigh,Irene M.

AU - Jackson,Sarah

AU - Storey,Alan

PY - 2010/11/17

Y1 - 2010/11/17

N2 - <p>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.</p>

AB - <p>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.</p>

KW - apoptosis

KW - Bak

KW - mitochondria

KW - phosphatase

KW - SIGNAL-REGULATED KINASE

KW - CYTOCHROME-C RELEASE

KW - MITOCHONDRIAL APOPTOSIS

KW - MASS-SPECTROMETRY

KW - OLIGOMERIZES BAK

KW - CELL-DEATH

KW - PROTEIN

KW - BCL-2

KW - PATHWAY

KW - INHIBITION

U2 - 10.1038/emboj.2010.244

DO - 10.1038/emboj.2010.244

M1 - Article

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 22

VL - 29

SP - 3853

EP - 3868

ER -