A role for PtdIns(4,5)P2 and PIP5Kalpha in regulating stress-induced apoptosis
A role for PtdIns(4,5)P2 and PIP5Kalpha in regulating stress-induced apoptosis
The phosphoinositide phosphatidylinositol 4, 5-bisphosphate (PtdIns(4,5)P2) is essential for many cellular processes and is linked to the etiology of numerous
human diseases [1–4]. PtdIns(4,5)P2 has been indirectly implicated as a negative regulator of apoptosis
[5–9]; however, it is unclear if apoptotic stimuli negatively regulate PtdIns(4,5)P2 levels in vivo. Here, we
show that two apoptotic-stress stimuli, hydrogen peroxide (H2O2) and UV irradiation, cause PtdIns(4,5)P2
depletion during programmed cell death independently of and prior to caspase activation. Depletion
of PtdIns(4,5)P2 is essential for apoptosis because
maintenance of PtdIns(4,5)P2 levels by overexpression of PIP5Ka rescues cells from H2O2-induced apoptosis. PIP5Ka expression promotes both basal and
sustained ERK1/2 activation after H2O2 treatment,
and importantly, pharmacological inhibition of ERK1/
2 signaling blocks PIP5Ka-mediated cell survival.
H2O2 induces tyrosine phosphorylation and translocation of PIP5Ka away from its substrate at the plasma
membrane, and both are dependent upon the activity
of c-src family kinases. Furthermore, constitutively
active c-src enhances tyrosine phosphorylation of
PIP5Ka in vivo and is sufficient for the translocation
of PIP5Ka away from the plasma membrane. These
observations demonstrate that certain apoptotic
stimuli initiate an essential signaling pathway
during cell death, and this pathway leads to caspaseindependent downregulation of PIP5Ka and its product PtdIns(4,5)P2.
Animals Apoptosis/drug effects/*physiology/radiation effects Caspases/metabolism Down-Regulation Enzyme Activation Green Fluorescent Proteins/analysis HeLa Cells Humans Hydrogen Peroxide/pharmacology Mice Mitogen-Activated Protein Kinase 1/physiology Mitogen-Activated Protein Kinase 3/physiology Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositol Phosphates/genetics/metabolism/*physiology Phosphorylation Phosphotransferases (Alcohol Group Acceptor)/*physiology Recombinant Fusion Proteins/analysis Signal Transduction Tyrosine/metabolism Ultraviolet Rays src-Family Kinases/physiology
1850-1856
Halstead, J. R.
019c9dab-c338-4f97-9318-353858ea82ac
van Rheenen, J.
64841b09-2f62-415e-944e-34170c6b0715
Snel, M. H.
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Meeuws, S.
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Mohammed, S.
ba6e34b4-419f-4b3d-b50a-2abdf8ce50c5
D'Santos, C. S.
544f8e9e-95e1-4d0b-9a72-312afe893eb3
Heck, A. J.
f15e1fc0-2c5a-4232-83b6-dcc9b042a228
Jalink, K.
81124fdb-185d-43c1-a659-cd22dd2d381c
Divecha, N.
5c2ad0f8-4ce7-405f-8a15-2fc4ab96d787
19 September 2006
Halstead, J. R.
019c9dab-c338-4f97-9318-353858ea82ac
van Rheenen, J.
64841b09-2f62-415e-944e-34170c6b0715
Snel, M. H.
68a0a7a3-d3c0-4261-a5df-af0d8499332c
Meeuws, S.
3e8a2a45-93b3-48ef-84b2-d0ca93b25e35
Mohammed, S.
ba6e34b4-419f-4b3d-b50a-2abdf8ce50c5
D'Santos, C. S.
544f8e9e-95e1-4d0b-9a72-312afe893eb3
Heck, A. J.
f15e1fc0-2c5a-4232-83b6-dcc9b042a228
Jalink, K.
81124fdb-185d-43c1-a659-cd22dd2d381c
Divecha, N.
5c2ad0f8-4ce7-405f-8a15-2fc4ab96d787
Halstead, J. R., van Rheenen, J., Snel, M. H., Meeuws, S., Mohammed, S., D'Santos, C. S., Heck, A. J., Jalink, K. and Divecha, N.
(2006)
A role for PtdIns(4,5)P2 and PIP5Kalpha in regulating stress-induced apoptosis.
Current Biology, 16 (18), .
(doi:10.1016/j.cub.2006.07.066).
Abstract
The phosphoinositide phosphatidylinositol 4, 5-bisphosphate (PtdIns(4,5)P2) is essential for many cellular processes and is linked to the etiology of numerous
human diseases [1–4]. PtdIns(4,5)P2 has been indirectly implicated as a negative regulator of apoptosis
[5–9]; however, it is unclear if apoptotic stimuli negatively regulate PtdIns(4,5)P2 levels in vivo. Here, we
show that two apoptotic-stress stimuli, hydrogen peroxide (H2O2) and UV irradiation, cause PtdIns(4,5)P2
depletion during programmed cell death independently of and prior to caspase activation. Depletion
of PtdIns(4,5)P2 is essential for apoptosis because
maintenance of PtdIns(4,5)P2 levels by overexpression of PIP5Ka rescues cells from H2O2-induced apoptosis. PIP5Ka expression promotes both basal and
sustained ERK1/2 activation after H2O2 treatment,
and importantly, pharmacological inhibition of ERK1/
2 signaling blocks PIP5Ka-mediated cell survival.
H2O2 induces tyrosine phosphorylation and translocation of PIP5Ka away from its substrate at the plasma
membrane, and both are dependent upon the activity
of c-src family kinases. Furthermore, constitutively
active c-src enhances tyrosine phosphorylation of
PIP5Ka in vivo and is sufficient for the translocation
of PIP5Ka away from the plasma membrane. These
observations demonstrate that certain apoptotic
stimuli initiate an essential signaling pathway
during cell death, and this pathway leads to caspaseindependent downregulation of PIP5Ka and its product PtdIns(4,5)P2.
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More information
Published date: 19 September 2006
Additional Information:
Halstead, Jonathan R van Rheenen, Jacco Snel, Mireille H J Meeuws, Sarah Mohammed, Shabaz D'Santos, Clive S Heck, Albert J Jalink, Kees Divecha, Nullin eng Research Support, Non-U.S. Gov't England 2006/09/19 Curr Biol. 2006 Sep 19;16(18):1850-6. doi: 10.1016/j.cub.2006.07.066.
Keywords:
Animals Apoptosis/drug effects/*physiology/radiation effects Caspases/metabolism Down-Regulation Enzyme Activation Green Fluorescent Proteins/analysis HeLa Cells Humans Hydrogen Peroxide/pharmacology Mice Mitogen-Activated Protein Kinase 1/physiology Mitogen-Activated Protein Kinase 3/physiology Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositol Phosphates/genetics/metabolism/*physiology Phosphorylation Phosphotransferases (Alcohol Group Acceptor)/*physiology Recombinant Fusion Proteins/analysis Signal Transduction Tyrosine/metabolism Ultraviolet Rays src-Family Kinases/physiology
Identifiers
Local EPrints ID: 480081
URI: http://eprints.soton.ac.uk/id/eprint/480081
ISSN: 0960-9822
PURE UUID: 27fde209-647f-4d93-9f04-6b7bce320534
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Date deposited: 01 Aug 2023 16:45
Last modified: 17 Mar 2024 03:47
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Contributors
Author:
J. R. Halstead
Author:
J. van Rheenen
Author:
M. H. Snel
Author:
S. Meeuws
Author:
S. Mohammed
Author:
C. S. D'Santos
Author:
A. J. Heck
Author:
K. Jalink
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