Kinase Function in Brain

Group leader

Eleanor Coffey
Research Director (Forskningschef) at Åbo Akademi University
Vice Director Turku Centre for Biotechnology
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)
+358-2-251 8808 (Fax Attn. Eleanor Coffey)
GSM: 348605

Marie Curie Initial Training Network

We are coordinating a Marie Curie Initial Training Network entitled Brain Imaging Return to Health (r’BIRTH) involving 9 research organisations across Europe.

This work is carried out in the context of depressive disorders and examines neurogenesis, synaptic plasticity and brain architecture changes in anxiety and depression (You Tube video). Our technology platform utilizes high-end imaging and proteomics approaches tailored for brain research and includes development of new optogenetic tools. The study will create a new generation of imaging probes for use in patients. For more information check out the r’BIRTH web page.

Additionally in this context of molecular mechanisms of pyschiatric disease, we participate in the nEUROskeleton consortium, a group of laboratories across Europe that studies the cytoskeleton in diseases of the nervous system.

Description of the research

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) is recognised as a player in a broad range of diseases including stroke and neurodegenerative and pyschiatric diseases, while the genes LRRK2 (PARK8) and PINK1 (PARK6) are Parkinson’s associated genes that encode protein kinases. Exactly how these proteins mediate neuronal death/survival responses in the brain remains largely unknown. (Click for video describing the structural basis of the binding specificity of JNK docking grooves).

Although targeting of protein kinases for drug-based therapy is already underway, our understanding of the pathophysiological mechanism of these molecules in disease as well as their normal function in the brain is in its infancy. Our lab has established a proteomics screen that identifies protein kinase substrates from brain tissue. Combining information on novel target identity with biochemical, genetic and imaging approaches has revealed unexpected functions for JNK in neocortex development and provided mechanistic insight on JNK action in neuronal disease.

In utero electroporated mouse brain showing dendritic field of GFP-MAP2 neurons in M1.

A similar investigation on LRRK2 targets is in progress. This has brought new insight regarding LRRK2 function that has broadened our understanding of Parkinson’s Disease at the molecular level and provided new ground for translational research including diagnostic test development. This work is funded by the the Finnish Funding Agency for Innovation (TEKES).

Group members

Prasannakumar Deshpande, Patrik Hollos, Francesca Marchisella, Artemis Varidaki, Ye Hong, Dani Flinkman, Lassi Lauren, Nikita Tiwari, Adrien Janssens, Siv Holmgren, Veronica Fagerholm. Individual information on group members can be found here Group.

Left to right: Hasan Mohammad, Patrik Hollos, Susanna Pyökäri, Dani Flinkman, Artemis Varidaki, Olavi Misin, Francesca Marchisella, Prasanakumar Deshpande, Eleanor Coffey.

Alumni (Group members and exchange students)

Sylvia Ortega-Martinez, Hasan Mohammad, Emilia Komulainen, Justyna Zdrojewska, Olavi Misin, Artur Padzik, Benny Björkblom, Hanna Heikelä, Vesa Hongisto, Wenrui Li, Elli Oksanen, Lihua Sun, Jenni Vainio, Nina Westerlund, Yubao Wang, Agniezka Bialek, Gunilla Hognas, Johanna Holmbom, Marit Jorgensen, Miikka Hurme, Julie Millour, Lenaig Marchand, Kimmo Mäkela, Iiris Nykanen, Annika Nymark, Annika Pienimaki, Emmy Rannikko, Maria Shariatmadari, Henna Sihvonen, Annika Smeds, Nina Smeds, Jenny Södermann, Rognoy Vibeke, Mats Österholm, Hanah Orellana, Ravi Adusumalli, Hung Phuoc, Behnoush Fourutan, Raghavendra Mysore.

Funding

FP7 Marie Curie-ITN Brain Imaging Return to Health, TEKES (Finnish Funding Agency for Innovation), Åbo Akademi University, Molecular Biosciences and UTUGS graduate school, Suomen Kultuurirahasto, Finnish Parkinson’s Association. Previous: EU-FP6 STREP and ToK, Sitra, CIMO, Juselius, Biocenter Finland, Academy of Finland.

Selected Publications

Mohammad, H#., Marchisella, F#., Ortega-Martinez, S.#,Hollos, P., Eerola, K., Komulainen, E., Kulesskaya, N.Freemantle, E., Fagerholm, V., Savbontaus, E., Rauvala, H., Peterson, B.D., van Praag, H., Coffey, E. JNK1 controls adult hippocampal neurogenesis and imposes cell autonomous control of anxiety behaviour from the neurogenic niche. Molecular Psychiatry. 2016, In press#equal contribution

Marchisella, F., Coffey, E.T. *, Hollos, P. Microtubule and microtubule associated protein anomalies in psychiatric disorders. Cytoskeleton. Special review issue on Emerging Concepts in Neuronal Cytoskeleton. 2016 in press

Padzik, A#, Deshpande, P#, Hollos, P#, Franker, M, Rannikko, E, Cai, D, Prus, P, Mågard, M, Westerlund, N, Verhey, K, James, P, Hoogenraad, C, Coffey, ET. KIF5C S176 phosphorylation regulates microtubule binding and transport efficiency in neurons. Frontiers in Cellular Neuroscience. 2016 in press. #equal contribution

Varidaki, A, Mohammad, H, Coffey, ET. Molecular Mechanisms of Depression. Systems Neuroscience in Depression. Elsevier Edited by Frodl, T. 2016 in press

Ortega-Martinez, S. A new perspective on the role of CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Frontiers in Molecular Neuroscience. 2015 26, 8,46.

Komulainen, E, Zdrojewska, J, Freemantle, E, Mohammad, H, Marchisella, F, Kulesskaya, N, Mysore, R, Deshpande, P, Michelson, K, Måberg, M, Rauvala, H, James, P, Coffey, E. JNK1 controls dendritic field size in L2/3 and L5 of the motor cortex, constrains soma size and influences fine motor coordination. Frontiers in Cellular Neuroscience. 2014 8, 272:

Coffey E.T.  Nuclear and cytosolic JNK signalling in neurons. Nature Reviews Neuroscience 2014 15(5):285-99. Pubmed

Zdrojewska J, Coffey ET. The impact of JNK on neuronal migration. Advances in Experimental Medical Biology. 2014;800:37-57. Review. Pubmed

Björkblom B*, Padzik A*, Mohammad H, Westerlund N, Komulainen E, Hollos P, Parviainen L, Papageorgiou AC, Iljin K, Kallioniemi O, Kallajoki M, Courtney MJ, Mågård M, James P, Coffey ET. JNK Phosphorylation of MARCKSL1 Determines Actin Stability and Migration in Neurons and in Cancer Cells. Molecular and Cellular Biology. 2012 32(17):3513-26. Pubmed

Jonsdottir K, Zhang H, Jhagroe D, Skaland I, Slewa A, Björkblom B, Coffey ET, Gudlaugsson E, Smaaland R, Janssen EA, Baak JP. The prognostic value of MARCKS-like 1 in lymph node-negative breast cancer. Breast Cancer Research and Treatment. 2012 Jul 8. [Epub ahead of print]

Mai, A., Veltel, S., Pellinen, T., Padzik, A., Coffey, E., Marjomäki, V., Ivaska, J. Competetive binding of Rab21 and p120RasGAP to integrins regulates receptor traffic and migration. Journal of Cell Biology. 194(2), 291-306, 2011.

Westerlund N, Zdrojewska J, Padzik A, Komulainen E, Björkblom B, Rannikko E, Tararuk T, Garcia-Frigola C, Sandholm J, Nguyen L, Kallunki T, Courtney MJ, Coffey ET. Phosphorylation of SCG10/stathmin-2 determines multipolar stage exit and neuronal migration rate. Nature Neuroscience. 14, (3), 305-13, 2011

Matlawska-Wasowska K, Finn R, Mustel A, O’Byrne CP, Baird AW, Coffey ET, Boyd A. The vibrio parahaemolyticus Type III secretion systems manipulate host cell MAPK for critical steps in pathogenesis. BMC Microbiology. Dec 30th, 2010

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 Neuroscience 10,(4):436-443

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

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

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

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

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

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