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Tyrosine dephosphorylation is required for Bak activation in apoptosis

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Tyrosine dephosphorylation is required for Bak activation in apoptosis. / Fox, Joanna L.; Ismail, Ferina; Azad, Abul; Ternette, Nicola; Leverrier, Sabrina; Edelmann, Mariola J.; Kessler, Benedikt M.; Leigh, Irene M.; Jackson, Sarah; Storey, Alan.

In: EMBO Journal, Vol. 29, No. 22, 17.11.2010, p. 3853-3868.

Research output: Contribution to journalArticle

Harvard

Fox, JL, Ismail, F, Azad, A, Ternette, N, Leverrier, S, Edelmann, MJ, Kessler, BM, Leigh, IM, Jackson, S & Storey, A 2010, 'Tyrosine dephosphorylation is required for Bak activation in apoptosis' EMBO Journal, vol 29, no. 22, pp. 3853-3868.

APA

Fox, J. L., Ismail, F., Azad, A., Ternette, N., Leverrier, S., Edelmann, M. J., Kessler, B. M., Leigh, I. M., Jackson, S., & Storey, A. (2010). Tyrosine dephosphorylation is required for Bak activation in apoptosis. EMBO Journal, 29(22), 3853-3868doi: 10.1038/emboj.2010.244

Vancouver

Fox JL, Ismail F, Azad A, Ternette N, Leverrier S, Edelmann MJ et al. Tyrosine dephosphorylation is required for Bak activation in apoptosis. EMBO Journal. 2010 Nov 17;29(22):3853-3868.

Author

Fox, Joanna L.; Ismail, Ferina; Azad, Abul; Ternette, Nicola; Leverrier, Sabrina; Edelmann, Mariola J.; Kessler, Benedikt M.; Leigh, Irene M.; Jackson, Sarah; Storey, Alan / Tyrosine dephosphorylation is required for Bak activation in apoptosis.

In: EMBO Journal, Vol. 29, No. 22, 17.11.2010, p. 3853-3868.

Research output: Contribution to journalArticle

Bibtex - Download

@article{cfd4213bbb8e444cb9361d9fabcb4b0b,
title = "Tyrosine dephosphorylation is required for Bak activation in apoptosis",
author = "Fox, {Joanna L.} and Ferina Ismail and Abul Azad and Nicola Ternette and Sabrina Leverrier and Edelmann, {Mariola J.} and Kessler, {Benedikt M.} and Leigh, {Irene M.} and Sarah Jackson and Alan Storey",
year = "2010",
volume = "29",
number = "22",
pages = "3853--3868",
journal = "EMBO Journal",
issn = "0261-4189",

}

RIS (suitable for import to EndNote) - Download

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 -

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