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Molecular Signalling
Research
Organisation and Function of Neuronal
Stress-activated Protein Kinase Pathways
Neuronal cells
possess a complex
architecture consisting of multiple subcellular compartments. Disease
states
place cells under stressful
conditions.  Stress-activated protein kinase pathways are widely
accepted
to play a significant role in cell death in and outside the nervous
system,
and drugs directly targeting stress activated protein kinases have been
under development for a number of years. However, recent work indicates
that these pathways also contribute to development, differentiation,
and
even survival and proliferation. This suggests that direct
stress-activated
protein kinase inhibitors may be of only limited use. In order to
exploit
the pathways for the development of novel neuroprotective drugs, it
will
be necessary to elucidate the mechanisms that organise these pathways
into
pools with neurodegenerative or
physiological functions within the complex structure of neuronal cells.
Only then can the neurodegenerative
activities of these pathways be selectively eliminated. It has been
suggested
that this may help reduce the neuronal death that contributes to
neurodegenerative
conditions such as Alzheimer’s and Parkinson’s diseases, increasingly
major
causes of death, disability and socioeconomic impact in society.
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Previous studies of mammalian
stress-activated MAPK pathway have revealed
the existence of a plethora of upstream regulators competent to recruit
this pathway. More recently, proteins with putative scaffolding actions
have been found. Such components could in principle have a number of
effects
on the associated upstream regulator, including (i) to potentiate its
ability
to activate the pathway, (ii) to restrict accessibility to activators,
(iii) to channel the downstream consequence to select targets and (iv)
to localise these properties to specific compartments within a cell. We
have observed that neuronal cells possess multiple pools of activity of
the JNK stress-activated protein kinase group, some associated with
development
and others with stress signalling. We have found that specific isoforms
are associated with these functionally different stress-activated
protein kinase pools. Our lab aims to elucidate how neuronal cells
compartmentalise
the endogenous components of the stress-activated protein kinase
pathway.
The mechanisms which maintain selective responsiveness to upstream
stimuli
and restricted downstream consequences are anticipated to be a fruitful
source of potential targets for neuroprotective strategies.
Our research is focused on three areas:
- Impact of post-synaptic density proteins on neuronal stress-activated
protein kinase signalling pathways (webpage in preparation)
- Small G-protein signalling pathways regulating stress-activated protein
kinases in neurons (webpage in preparation)
- Development and implementation of approaches to imaging intracellular
signalling pathways (webpage in preparation)
We are also responsible for the
Multimodal Imaging Core
specialised in high-throughput and high-resolution live cell imaging.
Major Collaborators
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Eleanor Coffey (Turku Centre for Biotechnology,
Åbo Akademi University and University of Turku, Finland)
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Thomas Herdegen (Department of Pharmacology,
University of Kiel, Kiel, Germany)
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Christophe Bonny (Xigen SA, Lausanne, Switzerland)
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Other members of the STRESSPROTECT consortium (www.neuroprotect.eu)
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Mark Spaller (Dept. of Molecular
Pharmacology, Physiology & Biotechnology, Brown University,
Providence, RI, USA)
Project Funding
Selected References
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Hellwig, C.T., Kohler, B.F., Lehtivarjo A.-K., Dussmann, H., Courtney,
M.J., Prehn, J.H. and Rehm, M. (2008) Real-time analysis of TRAIL/CHX-induced
caspase activities during apoptosis
initiation.
J. Biol. Chem. 2008 June 3
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Björkblom, B., Vainio, J.C.,
Hongisto, V., Herdegen, T., Courtney, M.J., Coffey, E.T. (2008) All JNKs
can Kill but Nuclear Localisation is Critical for Neuronal Death.
J.
Biol. Chem. 2008 May 12. |
pdf
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Hongisto, V., Vainio, J.C., Thompson, R., Courtney, M.J.,
Coffey, E.T. (2008) The Wnt pool of glycogen synthase kinase 3beta is
critical for trophic-deprivation-induced neuronal death.
Mol. Cell Biol. 28, 1515–1527
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pdf
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Westerlund, N., Zdrojewska, J., Courtney, M.J. and Coffey, E.T.
(2008) Superior cervical ganglion-10 protein as a molecular effector of
c-Jun N-terminal kinase 1: implications for the therapeutic targeting of
Jun N-terminal kinase in nerve regeneration.
Expert Opin. Ther. Targets. 12,
31-43. |
pdf
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Semenova, M.M., Mäki-Hokkonen, A.M.J., Cao,
J., Komarovski, V., Forsberg, K.M., Koistinaho, M. Coffey E.T. and
Courtney, M.J. (2007) Rho mediates calcium-dependent activation of
p38alpha and subsequent excitotoxic cell death.
Nat. Neurosci. 10, 436-443.
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pdf
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Tararuk, T., Östman N., Li, W., Padzik, A., Björkblom, B., Zdrojewska,
J., Hongisto, V., Herdegen, T., Konopka, W., Courtney, M.J. and Coffey,
E.T. (2006) JNK1 phosphorylation of SCG10 determines microtubule
dynamics and axodendritic length.
J. Cell Biol. 173, 265-277.
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pdf
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Björkblom, B., Östman, N., Hongisto, V., Komarovski, V., Filén,
J-J., Nyman, T.A., Kallunki, T., Courtney, M.J., and Coffey, E.T.
(2005) Constitutively active cytoplasmic c-Jun N-terminal kinase 1 is
a dominant regulator of dendritic architecture: role of
microtubule-associated protein 2 as an effector.
J. Neurosci. 25, 6350-6361.
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pdf
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Cao, J., Viholainen, J.I., Dart, C., Warwick, H.K., Leyland, M.L. and
Courtney, M.J. (2005) The PSD95–nNOS interface: a target for inhibition of
excitotoxic p38 stress-activated protein kinase activation and cell
death.
J. Cell. Biol. 168, 117-126.
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pdf
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Cao, J., Semenova, M.M.,
Solovyan, V.T., Han, J., Coffey,
E.T., Courtney, M.J. (2004) Distinct requirements for p38alpha ad JNK
stress-activated protein kinases in different forms of apoptotic
neuronal
death.
J. Biol. Chem., 34, 35903-35913. |
pdf
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Hongisto, V., Smeds, N., Brecht S., Herdegen,
T., Courtney, M.J. and
Coffey, E.T. (2003) Lithium blocks the c-Jun
stress
response and protects neurons via its action on glycogen synthase
kinase
3.
Mol.
Cell Biol. 23, 6027-6036. |
pfd
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Tran, S.E.F., Meinander, A, Holmström,
T.H., Rivero-Müller,
A., Heiskanen, K.M., Linnau, E.K., Courtney, M.J., Mosser, D.D.
Sistonen,
L. Eriksson, J.E. (2003) Heat stress downregulates FLIP and sensitizes
cells to Fas receptor-mediated apoptosis.
Cell
Death Differ. 10, 1137-1147.
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Coffey, E.T., Smiciene, G., Hongisto, V., Cao,
J., Brecht S., Herdegen,
T. and Courtney, M.J. (2002) c-Jun N-terminal protein kinase (JNK) 2/3 is
specifically activated by stress, mediating c-Jun activation, in the
presence of constitutive JNK1 activity in cerebellar neurons.
J.
Neurosci. 22, 4335-4345. |
pdf
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Solovyan, V., Bezvenyuk, Z., Salminen, A.,
Austin, C.A. and Courtney M.J. (2002) The role of topoisomerase II in the
excision of DNA loop domains during apoptosis.
J.
Biol. Chem. 277, 21458-21467.
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Coffey, E.T., Hongisto, V.,
Dickens, M., Davis, R.J. and Courtney, M.J.
(2000) Dual roles for c-Jun N-terminal kinase in developmental and
stress
responses in cerebellar granule neurons.
J.
Neurosci. 20, 7602-7613. |
pdf
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Courtney, M.J. and Coffey, E.T. (1999) The
mechanism of Ara-C induced
apoptosis of differentiating cerebellar granule neurons.
Eur.
J. Neurosci. 11, 1073-1084.
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Coffey, E.T., Åkerman, K.E.O. and
Courtney, M.J. (1997) Brain derived neurotrophic factor induces a rapid
upregulation of synaptophysin and tau proteins via the neurotrophin
receptor TrkB in rat cerebellar granule cells
Neurosci.Lett.
227, 177-180.
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Coffey, E.T. and Courtney, M.J. (1997) Regulation of
SAP kinases in CNS neurons.
Biochem.
Soc. Trans. 25, S568.
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Courtney, M.J., Åkerman, K.E.O. and
Coffey, E.T. (1997) Neurotrophins
protect cultured cerebellar granule neurons against the early phase of
cell death by a two-component mechanism.
J.
Neurosci.17, 4201-4211.
Updated 29.8.2008 |
