Tyrosine kinases can affect growth, differentiation, and survival of neurons and glia. Furthermore, in animal models, they have been shown to affect learning and memory. Receptor tyrosine kinases transduce a variety of extracellular signals resulting in activation of their intracellular tyrosine kinase domain. A new member of this receptor family, Tyro-3, is of special interest given its localization, structure and potential activation by neural activity. Preliminary evidence presented here indicates that Tyro-3 is preferentially localized to dendrites of cortical and hippocampal neurons of area Ca1. Unique among receptor tyrosine kinases is the strong structural similarity between its extracellular domains and those of neural cell adhesion molecules suggesting a functional role in adhesive cell-cell interactions. These interactions are crucial for establishing correct functional neuroanatomy during development and in the adult animal. Tyro-3 can be phosphorylated by the binding of its ligand gas6 to the extracellular domain of this receptor. Gas6 (growth arrest specific gene-6) is a molecule shown to prevent apoptosis and to have mitogenic properties, functions that in the nervous system could be mediated by Tyro-3. As first shown in this proposal, Tyro-3 can also become activated by the excitatory neurotransmitter glutamate when added to hippocampal cultures. We propose: (a) To determine the developmental patterns of expression of Tyro-3 and its ligand gas6 in the nervous system, and the cellular and subcellular distribution of Tyro-3. This will provide important initial cues for elucidating cellular functions of the gas6/Tyro-3 ligand/receptor pair and clarify its involvement in synaptic or extrasynaptic processes. (b) To test the hypothesis that Tyro-3 can bind to itself or other molecules at the cell surface functioning as a cell adhesion molecule, and to examine how gas6 can modulate these interactions. We will also determine if adhesive events result in activation of the tyrosine kinase domain. (c) To identify the critical parameters that affect tyrosine phosphorylation of Tyro-3 upon stimulation of hippocampal neurons by the excitatory neurotransmitter glutamate, and to determine if Tyro-3 activation occurs in the absence of extracellular binding ligands. Through these efforts we hope to uncover the role of Tyro-3 in molecular mechanisms of cell adhesion, intracellular signaling and neuroplasticity in the normal and diseases nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS037471-04
Application #
6477222
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Tagle, Danilo A
Project Start
1998-12-01
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
4
Fiscal Year
2002
Total Cost
$107,335
Indirect Cost
Name
Indiana University Bloomington
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
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Binder, Michele D; Cate, Holly S; Prieto, Anne L et al. (2008) Gas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced demyelination. J Neurosci 28:5195-206
Prieto, A L; O'Dell, S; Varnum, B et al. (2007) Localization and signaling of the receptor protein tyrosine kinase Tyro3 in cortical and hippocampal neurons. Neuroscience 150:319-34
Hall, Michael O; Obin, Martin S; Prieto, Anne L et al. (2002) Gas6 binding to photoreceptor outer segments requires gamma-carboxyglutamic acid (Gla) and Ca(2+) and is required for OS phagocytosis by RPE cells in vitro. Exp Eye Res 75:391-400
Hall, M O; Prieto, A L; Obin, M S et al. (2001) Outer segment phagocytosis by cultured retinal pigment epithelial cells requires Gas6. Exp Eye Res 73:509-20
Prieto, A L; Weber, J L; Lai, C (2000) Expression of the receptor protein-tyrosine kinases Tyro-3, Axl, and mer in the developing rat central nervous system. J Comp Neurol 425:295-314