Receptor tyrosine kinases in the development, disorder and regulation of the nervous system

Laboratory of Neural Signalling 
directed by
Dr. Susan O. Meakin
Cell Biology and Stem Cell Biology Groups
The Robarts Research Institute

J. Allyn Taylor Centre for Cell Biology

Program in Regenerative Medicine, Krembil Centre for Stem Cell Biology


Full Professor

The Department of Biochemistry
 http://www.biochem.uwo.ca/

  The Graduate Program in Neuroscience
http://www.uwo.ca/neuroscience/

The University of Western Ontario, London, Ontario 
The Meakin Lab

<>     The Meakin lab is investigating mechanisms regulating functional interactions of the 'TrkA'  protooncogene.  TrkA is a ligand activated tyrosine kinase receptor for nerve growth factor (NGF), a molecule which is important in the growth, development and survival of the sympathetic and the pain and temperature sensitive sensory neurons of the peripheral nervous system as well as the cholinergic neurons of the basal forebrain which are involved in memory.  One of the interesting problems inherent to this receptor is the fact that it can elicit different functional responses in different cell types.  NGF-stimulated TrkA activates a mitogenic response in non-neuronal cells such as fibroblasts; in contrast, the same ligand-receptor combination stimulates differentiation in cells of neuronal lineage.  How then does one receptor stimulate two phenotypically different responses depending on the cell in which it is expressed?  It is the answer to this question which was the initial focus , and remains a primary focus, of my lab.  This question was the driving force behind our identification of the FRS2 adapter and in characterizing its role in neurotrophin-dependent neurite outgrowth.  Essentially,  FRS-2 is an essential component to the process of NGF-dependent mitotic arrest.  The role of FRS-2, and a related signaling adapter termed FRS-3, in the regulation of proliferation versus differentiation is being investigated by a variety of cell and molecular biology approaches as well as in transgenic mouse model systems. 
    Through efforts to clone and characterize additional novel signalling molecules that interact with the Trk family of receptors, TrkA, TrkB and TrkC, and which are important to the process of neuronal differentiation and/or neuronal function, we have identified and are investigating several additional, new aspects. 
     (1) Nesca: This molecule is expressed in the nervous system and which appears to facilitate neurotrophin-dependent differentiation, particularly at low concentrations of ligand.  Interestingly, this molecule translocates from the cytosol to the nucleus in response to neurotrophin stimulation.  Efforts to determine whether this molecule functions as a novel neurotrophin transcriptional activator are underway. 
     (2) The neuronal Shc adapters, ShcB and ShcC, as well as the brain-specific nucleotide exchange factor for Ras, RasGrf1.   RasGrf1 is involved in synaptic transmission and long-term memory and interacts with the NR2B subunit of the NMDA receptor to stimulate long-term depression..  ShcC on the other hand, appears to regulate the  tyrosine phosphorylation status of NR2B which regulates its retension and activity in the post-synaptic membrane.  Our recent data suggests that TrkB's activation and recruitment of ShcC and RasGrf1 in the post-synaptic neuron can regulate the activation status of the NMDA receptor which is the physiological gate keeper of learning and memory.  Thus, we are exploring mechanisms of receptor cross-talk between TrkB and NMDAR involved in the  mechanisms  regulating synaptogenesis and memory development.  
     (3) Lastly, we have identified a novel mechanism by which TrkA induces death in medulloblastoma tumors (a childhood tumor in the brain) that is characteristic of a cell death process termed autophagy, not apoptosis.  We are in the process of determining how this signaling process is regulated, the mechanisms involved and whether this process can be used to kill other types of neural tumors such as glioblastomas and astrocytomas.
      These studies represent a divserse set of interests through which we hope to facilitate research in the field, both our own and others, that will improve our increasing  understanding of the multiplicity of roles that the Trk receptors can serve during neuronal growth and development as well as perturbations in these responses that may underlie some forms of neuronal degeneration, tumor development and learning disorders.



Group leader:
Dr. Susan O. Meakin
    B. Sc. (Honors, Microbiology; U. Guelph)
     Ph.D. (Molecular and Medical Genetics, U. of Toronto)
     Post Doc. (Neurobiology, Stanford University)
Researchers:
James I.S. MacDonald, PhD, Senior Research Associate
Chunhui Li, Research Technician
Sara LeMay, Research Technician
Todd Hryciw, PhD. Post-Doctoral Fellow
Sandy Vascotto, PhD., Post-Doctoral Fellow
Kim Robinson, B.Sc., RPsgT,  Ph.D. candidate (PREA, OGSST support) (Neuroscience)
Jennifer Gerasimoff, M.Sc., candidate (Biochemistry)
Jennifer Forsyth,
M.Sc., candidate (Biochemistry)
Ian Grant, M.Sc., candidate (Biochemistry)
Renee Phillips,
M.Sc., candidate (Neuroscience)
Jupinder Bains,
B.Sc. candidate (Biochemistry), Summer student and 4th yr Thesis student
 
Former trainees:
Hui-Yu Liu, Ph.D., Post Doctoral Fellow (CIHR fellowship)
Li Zhou ,
Ph.D. PostDoctoral Fellow (PREA support)

Rosslynn Miller-Lee, M.Sc. (Biochemistry)
Scott Dixon, M.S. (Neuroscience)
Ela A. Gryz,PhD. (Neuroscience)

Current Research Support                                                                  
The Cancer Research Society (CRS) - 2 grants  --> Click to check out   Meakin CRS Newsletter  July 2007
ORDCF/Krembil Funding for Stem Cell Research
The Natural Science and Engineering Research Council of Canada   


The Canadian Institutes of Health Research                                                     
                       NSERC              

Graduate and Post-Doctoral Positions Available
(1) To study the role of the FRS3 signaling adapter in the regulation of proliferation/differentiation in neuronal and stem cell cultures, in the developing nervous system of transgenic mice and in neuronal tumors.  Context specific FRS3 binding proteins will be isolated and identified by mass spectroscopy.
(2) To study the role of Nesca in neurotrophin-induced neurite outgrowth, its mechanism of nuclear transport and the  molecules that it regulates at the nuclear membrane.  Adeno and lentiviral approaches are in use to assay dominant negative and siRNA constructs in primary neurons.  Nesca binding  protiens will also be isolated and identified by mass spectroscopy.
(3) To study mechanisms of TrkB:NMDAR receptor cross-talk in hippocampal neurons.

PDF applicants should have a strong background in two or more of the following areas: molecular biology, primary cell culture, signaling/biochemistry, neural development. A recent Ph.D. in Physiology, Molecular Biology, Biochemistry, Neuroscience, Genetics, or a related field, is required along with at least 2 good to excellent quality first author publications.

Graduate school applicants with a strong interest in biomedical research and undergraduate training in related fields are also encouraged to apply


Recent Publications

Li, C., J.I.S. MacDonald, T. Hryciw, P. H. Anborgh, A. Lin and S.O. Meakin. 2007. TrkA Activates Death by Autophagy in Medulloblastoma Cells. Cell Death and Differentiation (submitted).

Woronowicz, A., S.R. Amith, V.W. Davis, K.De Vusser, W. Laroy, R. Contreras, S.O. Meakin and M.R. Szewczuk. 2007. Trypanosome trans-sialidase mediates neuroprotection against oxidative stress, serum/glucose deprivation and hypoxia-induced neurite retraction in Trk-expressing PC12 cells. Glycobiology (in press).

Dixon, S.J., J.I.S. MacDonald, K. N. Robinson,  C.J. Kubu and S.O. Meakin. 2006. Trk Receptor Binding and Neurotrophin/Fibroblast Growth Factor (FGF)-Dependent Activation of the FGF Receptor Substrate 3. Biochim. Biophys. Acta 1763: 366-380..

Liu, H.Y., J.I.S. MacDonald, T. Hryciw, C. Li and S.O. Meakin. 2005. Human Tid1 Associates with Trk Receptor Tyrosine Kinases and Regulates Neurite Outgrowth in nnr5-TrkA Cells.  J. Biol. Chem. 280: 19461-19471.

Robinson, K.N., K. E. Manto, R.J. Buchsbaum, J. I. S. MacDonald and S.O. Meakin.  2005.  Neurotrophin-Dependent Tyrosine Phosphorylation of Ras Guanine-releasing Factor 1 and Associated Neurite Outgrowth is Dependent on the HIKE Domain of TrkA. J. Biol. Chem. 280: 225-235.

MacDonald, J.I.S., C. J. Kubu and S.O. Meakin. 2004. Nesca, a Novel Adapter, Translocates to the Nuclear Envelope and Regulates Neurotrophin-Induced Neurite Outgrowth.  J. Cell Biology. 164: 851-862.

Gryz, E.A. and S.O. Meakin. 2003. Acidic Amino Acid Substitution of the Activation Loop Tyrosines in TrkA Supports Nerve Growth Factor-dependent, but not Nerve Growth factor-independent, Differentiation and Cell Cycle Arrest in the Human Neuroblastoma cell line, SY5Y. Oncogene 22: 8774-85.

Zhou, L., K. McDougall, C. Kubu, J. M. Verdi and S.O. Meakin. 2003. Genomic Organization and Comparative Sequence Analysis of the Mouse and Human FRS2, FRS3 genes. Mol. Biol. Report  30: 15-25. 

Ranzi, V., S. O. Meakin, C. Miranda, P. Mondellini, M. A. Pierotti and A. Greco. 2003. The Signalling Adapters FRS2 and FRS3 are substrates of the Thyroid TRK Oncoproteins. Endocrinology 144: 922-928.

Liu, H-Y. and S.O. Meakin. 2002. ShcB and ShcC Activation by the Trk Family of Receptor Tyrosine Kinases.  J. Biol. Chem 277: 26046-26056. 

Zeng, G. and S.O. Meakin. 2002. Overexpression of the Signaling Adapter FRS-2 Reconstitutes the Cell Cycle Deficit of a Nerve Growth Factor Non-Responsive TrkA Receptor Mutant. J. Neurochem. 81: 820-831.

MacDonald, J.I.S., E.A. Gryz, C. J. Kubu, J.M. Verdi and S.O. Meakin. 2000 . Direct Binding of the Signaling Adapter Protein, Grb2, to the Activation Loop Tyrosines on the Nerve Growth Factor Receptor Tyrosine Kinase, TrkA.  J. Biol. Chem. 274: 18226-18233. 

Gryz, E.A. and S.O. Meakin. 2000. Acidic Substitution of the Activation Loop Tyrosines in TrkA Supports Nerve Growth Factor -Independent Cell Survival and Neuronal Differentiation. Oncogene 19: 417-430. 

Meakin , S.O., J.I.S. MacDonald, E.A. Gryz, C.J. Kubu and J.M. Verdi. 1999 . The Signaling Adapter Protein FRS-2 Competes with Shc for Binding to the Nerve Growth Factor Receptor, TrkA: A Model for Discriminating Proliferation and Differentiation. J. Biol. Chem. 274: 9861-9871.

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Contact information
Laboratory of Neural Signalling
Cell Biology and Stem Cell Biology Groups
The Robarts Research Institute
P.O. Box 5015, 100 Perth Drive
London, Ontario N6A 5K8 CANADA 

Tel:  1-519-663-5777 x34304 (SOM)
Fax: 1-519-663-3314 or 663-3789
 
 

email me
smeakin@robarts.ca

Updated August 2nd, 2007
Copyright © 2007

 



 

The Robarts Research Institute


 

Navigational links for The Department of Biochemistry are located at the bottom of this page.
 


 
 


 
 


   


 

Neurotrophin Research
Cell Signalling  
Novel Gene Discovery  
Stem cell research
Gene targeting
Transgenic Mice
Viral-mediated Gene Transfer
Primary Neuronal Cultures

   TrkA induced Autophagy
in Daoy Medulloblastoma cells

autophagy

              NGF-dependent 
   mobilization of Nesca (green)
            and TrkA (red)

     

               NGF-dependent 
     association of Nesca with 
              nuclear pores

   
 

        PC12 cells (-) NGF

                 

PC12 cells (+) NGF

  


Primary Mouse Cortical Neurons Infected with an FRS2 Expressing
Adenovirus