Receptor tyrosine kinases in the development, disorder and regulation of the nervous system
The Robarts Research Institute
J. Allyn Taylor Centre for Cell Biology
Program in Regenerative Medicine, Krembil Centre for Stem Cell Biology
University of Western Ontario, London, Ontario
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.
Dr. Susan O. Meakin
B. Sc. (Honors, Microbiology; U. Guelph)Researchers:
Ph.D. (Molecular and Medical Genetics, U. of Toronto)
Post Doc. (Neurobiology, Stanford University)
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
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)
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
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
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
in biomedical research and undergraduate training in related fields are
also encouraged to apply
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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Laboratory of Neural SignallingThe Robarts Research Institute
Cell Biology and Stem Cell Biology Groups
P.O. Box 5015, 100 Perth Drive
London, Ontario N6A 5K8 CANADA
Updated August 2nd, 2007
The Robarts Research Institute
Novel Gene Discovery
Stem cell research
Viral-mediated Gene Transfer
Primary Neuronal Cultures
TrkA induced Autophagy
in Daoy Medulloblastoma cells
PC12 cells (-) NGF
PC12 cells (+) NGF