Kinase Function in Brain
Protein Kinase Regulation of Brain Development and Disease
Group Leader
Eleanor Coffey, Ph.D.
Academy Research Fellow
eleanor.coffey(at)btk.fi
Contact Information
Turku Centre for Biotechnology
P.O. Box 123, BioCity
(Street adr. Tykistökatu 6 B)
FIN-20521 Turku, Finland
+358-2-333 8605 (Eleanor Coffey)
+358-2-333 8000 (Fax Attn. Eleanor Coffey)
GSM: 348605
Front row, left to right: Emilia Komulainen, Justyna Zdrojewska, Hanna Heikelä, Eleanor Coffey. Back row, left to right: Prasannakumar Deshpande, Hasan Mohammed, Raghavendra Mysore, Lihua Sun, Artur Padzik.
Freshly isolated hippocampal neurons stained for MAP2 (yellow) and DNA (blue). MAP2 is a high molecular weight protein that provides structural stability to dendrites. Studies in the lab examine how postranslational modifications of proteins such as MAP2 can influence dendrite and spine development, ultimately affecting behavioural outcome.
Neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease are characterised by the irreversible loss of nerve cell function. The protein kinases c-Jun N-terminal kinase (JNK) and glycogen synthase kinase-3 (GSK-3) are recognised as players in a broad range of diseases including stroke and neurodegenerative disease. However exactly how these proteins mediate neuronal death in the brain remains largely unknown. While targeting of protein kinases for drug-based therapy is already underway, our understanding of the physiological functions of these molecules in the brain is in its infancy. Our lab established a proteomics screen for identification of protein kinase substrates in the brain. Using this screen we have uncovered several novel protein kinase targets. The identification of targets combined with biochemical, genetic and imaging approaches have revealed unexpected functions for JNK in neocortex development and provided mechanistic insight to JNK action in neuronal disease.
We have more recently commenced a screen for targets of leucine rich repeat kinase 2 (LRRK2). Mutations in LRRK2 are the most common cause of late-onset Parkinson's disease. While these mutations confer a gain of function in LRRK2 kinase activity, the substrates for this kinase remain elusive. Our screen should reveal much needed information on the normal function of LRRK2 in the brain, and we are hopeful that the discovery of effectors of LRRK2 will pave the way for increased molecular insight to Parkinson's disease.
Projects
Multifunctional JNK action in neurons
Molecular details of GSK-3 function in neuronal death
Current lab members
Artur Padzik, Justyna Zdrojewska, Emilia Komulainen, Minna Tuittila, Hanna Heikelä, Raghavendra Mysore, Lihua Sun, Prasannakumar Deshpande, Hasan Mohammed.
Alumni
Benny Björkblom, Vesa Hongisto, Wenrui Li, Emmy Rannikko, Nina Smeds, Jenni Vainio, Nina Westerlund.
Funding
The Academy of Finland, the Sigrid Juselius Foundation, Åbo Akademi University, EU 6th framework: ToK grant: GAMIDI and STRESSPROTECT, Sitra, CIMO, the Finnish Graduate School of Neurosciences, the Drug Discovery Graduate School.
Recent publications
Microtubule stabilization by BMP receptor-mediated scaffolding of JNK promotes dendrite formation. Podkowa M, Zhao X, Chow CW, Coffey ET, Davis RJ, Attisano L. Molecular and Cellular Biology. 2010
Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin. (2009) Morfini GA, You YM, Pollema SL, Kaminska A, Liu K, Yoshioka K, Björkblom B, Coffey ET, Bagnato C, Han D, Huang CF, Banker G, Pigino G, Brady ST. Nature Neuroscience. 12(7):864-71.
Waetzig, V, Wacker, U, Haeusgen, Björkblom,B, Courtney, M.J., Coffey, E.T. Herdegen, T. (2009) Concurrent protective and destructive signalling of JNK2 in neuroblastoma cells. Cellular Signalling. 873-880.
Naumanen, T., Johansen, L.D., Coffey, E.T., Kallunki, T. (2008) Loss of function of IKAP/ELP1: Could neuronal migration defect underlie familial disautonomia? Cell Adhesion and Migration. Vol.2, Issue 4.
Benny Björkblom, Jenni C. Vainio, Vesa Hongisto, Thomas Herdegen, Michael Courtney, Eleanor Coffey. (2008) All JNKs can kill but nuclear localization is critical for neuronal death. Journal of Biological Chemistry. 283(28)19704-13.
Hongisto, V., Vainio, J.C., Thompson, R., Courtney, M.J., Coffey, E.T. (2008) The Wnt pool of GSK-3-beta is critical for trophic deprivation induced neuronal death. Molecular and Cellular Biology 28(5)1515-27. PDF
Dan Johansen, L., Naumanen, T., Knudsen, A., Westerlund, N., Gromova, I., Junttila, M., Nielsen, C., Bottzauw, T., Tolkovsky, A., Westermarck, J., Coffey, E.T., Jäättelä, M., Kallunki, T. (2008) IKAP localizes to membrane ruffles with filamin A and regulates actin cytoskeleton organization and cell migration. Journal of Cell Science 121(6) 854-64.
Westerlund, N., Zdrojewska, J., Courtney, M.J., Coffey, E.T. (2008) SCG10 as a molecular effector of JNK1: Implications for the therapeutic targeting of JNK in nerve regeneration. Expert Opinion on Therapeutic Targets 12(1):31-43. PDF
Semenova, M.M., Mäki-Hokkonen, A.M.J., Cao, J., Komarovski, V., Forsberg, M., Koistinaho, M., Coffey, E.T., Courtney, M.J. (2007) Rho mediates calcium-dependent activation of p38alpha and subsequent excitotoxic cell death. Nature Neuroscience10,(4):436-443
This article was selected by Faculty 1000, Biology, Factor 3.0. Recommended reading. "This study demonstrates, for the first time, that the small GTPase Rho is an essential component of the excitotoxic cell death pathway. Excitotoxic neuronal death contributes to many neurological disorders and is known to involve calcium influx and stress-activated protein kinases, such as p38alpha, as signaling mediators. In this paper, the authors show that Rho is activated in rat neurons upon calcium influx and in the mouse cerebral cortex during ischemia. Rho activity was shown to be needed for glutamate-induced p38alpha activation and ensuing neuronal death. Furthermore, expression of active Rho alone was sufficient to induce the excitotoxic pathway leading to neuronal death in experimental models. Thus, targeting Rho might provide means for novel future therapeutics". Kristiina Vuori.
Tararuk, R., Östman, N., Li, W., Björkblom, B., Padzik, A., Zdrojewska, J., Hongisto, V., Herdegen, T., Konopka, W., Courtney, M.J., Coffey, E.T. (2006) JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length. Journal of Cell Biology 173(2):265-77 PDF
This article was selected by Faculty of 1000, Biology Factor 6.0. Must Read! "A variety of non-nuclear targets of c-Jun NH(2)-terminal kinases (JNKs) have been described, but this is one of the most convincing reports that JNKs indeed control microtubule dynamics via stathmin-like proteins in neurons. Although JNKs are defined as 'stress responsive' MAPKs in tissue culture, they actually regulate developmental changes involving cell movement and migration (from Drosophila to man). This is a nice example of using biochemistry through to cell biology and mouse transgenics to validate a kinase target." Ed Manser.
Björkblom, B., Östman, N., Hongisto, V., Komarovski, V., Filen, J., Nyman, T., Kallunki, T., Courtney, M., Coffey, E. (2005) Constitutively active cytoplasmic JNK1 is a dominant regulator of dendritic architecture; role of MAP2 as an effector. Journal of Neuroscience 25(27):6350-6361
PDF
Yang J, Lindahl M, Lindholm P, Virtanen H, Coffey E, Runeberg-Roos P, Saarma M. (2004) PSPN/GFRalpha4 has a significantly weaker capacity than GDNF/GFRalpha1 to recruit RET to rafts, but promotes neuronal survival and neurite outgrowth. FEBS Lett. 569:267-271
Cao J, Semenova MM, Solovyan VT, Han J, Coffey ET, Courtney MJ. (2004) Distinct requirements for p38alpha and c-Jun N-terminal kinase stress-activated protein kinase s in different forms of apoptotic neuronal death. Journal of Biological Chemistry 279:35903-35913
Hongisto V, Smeds N, Brecht S, Herdegen T, Courtney MJ, Coffey ET. (2003) Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. Molecular Cell Biology 23:6027-6036
PDF
Coffey E.T., Smiciene G., Hongisto V., Cao J., Brecht S., Herdegen T., 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. Journal of Neuroscience 22:4335-4345
PDF
Hietakangas V, Elo I, Rosenstrom H, Coffey ET, Kyriakis JM, Eriksson JE, Sistonen L. (2001) Activation of the MKK4-JNK pathway during erythroid differentiation of K562 cells is inhibited by the heat shock factor 2-beta isoform. FEBS Lett. 505:168-172
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. Journal of Neuroscience 20, 7602–7613
PDF
Courtney, M.J. and Coffey, E.T. (1999) The mechanisms of ARA-C induced apoptosis of differentiating cerebellar granule neurons. European Journal of Neuroscience. 11:1073-1084
Courtney, M.J., Åkerman, K.E.O. and Coffey, E.T. (1997) Neurotrophins protect cultured cerebellar granule cells against the early phase of cell death by a two-component mechanism. Journal of Neuroscience 17, 4201-4211
Coffey ET, Akerman KE, Courtney MJ. (1997) Brain derived neurotrophic factor induces a rapid upregulation of synaptophysin and tau proteins via the neurotrophin receptor TrkB in rat cerebellar granule cells. Neuroscience Letters. 227:177-180