During the development of the nervous system, a number of cellular processes which include cell proliferation, cell differentiation, cell adhesion, cell migration and cell death are required for the correct formation of neural structures and to obtain functional and reproducible connectivity between them. In the nervous system some of these cellular processes have been shown to be mediated or modulated by growth factors and their receptors. The receptors transduce responses upon activation its ligand through their tyrosine kinase domain the cytoplasmic tail. Examples of such growth factors/receptor pairs are NGF/trk, BDNK/trkB, and NT3/trkC. A yet uncharacterized receptor Tyro-3, belongs to this class and is the subject of our study. The overall goal of this project is to understand some of the functions, primarily in cell adhesion and to identify signal transduction pathways affected by the tyrosine kinas Tyro-3. This receptor has two immunoglobulin-like repeats and two fibronectin type-III repeats in its extracellular portion and intracellularly a functional tyrosine kinase domain, shown to be phosphorylated upon binding of its known ligand gas-6. We will determine the ultrastructural localization of Tyro-3 in the hoppocampus, in order to establish a possible role of Tyro-3 in synaptogenesis and synaptic plasticity. Preliminary data suggests that the Tyro-3 protein and mRNA are preferentially localizd in the dendritic layer of CA1 neurons. This structure has been demonstrated to be crucial for the establishment of short term memory and to be affected in Alzheimers disease. We will also analyze the cell adhesive properties of Tyro-3 and the ability of this adhesion to affect its kinase activity. Cel l adhesion plays a major role in neuronal patterning during development and can affect remodeling of synaptic connections in the adult CNS. We will study the observation that Tyro-3 is phosphorylated upon addition of glutamate to hippocampal neurons in culture. Through these efforts we hope to understand the role of Tyro-3, one of the few nervous ysstem specific tyrosine kinases described so far, and gain insight into the role played by tyrosine kinases in general in the signal transduction events important for the development and functioning of the nervous system.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR004050-12
Application #
6354285
Study Section
Project Start
2000-05-01
Project End
2001-04-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
12
Fiscal Year
2000
Total Cost
$38,473
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Funakoshi, Shunsuke; Miki, Kenji; Takaki, Tadashi et al. (2016) Enhanced engraftment, proliferation, and therapeutic potential in heart using optimized human iPSC-derived cardiomyocytes. Sci Rep 6:19111
Rubio-Marrero, Eva N; Vincelli, Gabriele; Jeffries, Cy M et al. (2016) Structural Characterization of the Extracellular Domain of CASPR2 and Insights into Its Association with the Novel Ligand Contactin1. J Biol Chem 291:5788-802
Yin, Xinghua; Kidd, Grahame J; Ohno, Nobuhiko et al. (2016) Proteolipid protein-deficient myelin promotes axonal mitochondrial dysfunction via altered metabolic coupling. J Cell Biol 215:531-542
Zhao, Claire Y; Greenstein, Joseph L; Winslow, Raimond L (2016) Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network. J Mol Cell Cardiol 91:215-27
Rajagopal, Vijay; Bass, Gregory; Walker, Cameron G et al. (2015) Examination of the Effects of Heterogeneous Organization of RyR Clusters, Myofibrils and Mitochondria on Ca2+ Release Patterns in Cardiomyocytes. PLoS Comput Biol 11:e1004417
Schachtrup, Christian; Ryu, Jae Kyu; Mammadzada, Könül et al. (2015) Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-? signaling and astrocyte functions. Nat Neurosci 18:1077-80
Sanders, Matthew A; Madoux, Franck; Mladenovic, Ljiljana et al. (2015) Endogenous and Synthetic ABHD5 Ligands Regulate ABHD5-Perilipin Interactions and Lipolysis in Fat and Muscle. Cell Metab 22:851-60
Takeshima, Hiroshi; Hoshijima, Masahiko; Song, Long-Sheng (2015) Ca²? microdomains organized by junctophilins. Cell Calcium 58:349-56
Mills, Elizabeth A; Davis, Chung-ha O; Bushong, Eric A et al. (2015) Astrocytes phagocytose focal dystrophies from shortening myelin segments in the optic nerve of Xenopus laevis at metamorphosis. Proc Natl Acad Sci U S A 112:10509-14
Kim, K-Y; Perkins, G A; Shim, M S et al. (2015) DRP1 inhibition rescues retinal ganglion cells and their axons by preserving mitochondrial integrity in a mouse model of glaucoma. Cell Death Dis 6:e1839

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