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Characterization of the Protein Tyrosine Kinase Tyro-3 and Its Ligand Gas6

A.L. Prieto

Receptor protein tyrosine kinases and their ligands play important roles in the nervous system in cell proliferation, differentiation, and survival; activity-dependent regulation of neural plasticity; and the establishment of topographic maps during development. These functions are achieved by transduction of a variety of extracellular signals, such as the binding of a growth factor to its receptor that results in activation of the intracellular tyrosine kinase domain of the receptor and initiates a cascade of downstream events. We are interested in discovering potential functions in the nervous system of one such receptor, Tyro-3, and of one of its ligands, Gas6.

Tyro-3 belongs to the Axl subfamily of receptors. Members of this family have 2 immunoglobulin-like domains and 2 fibronectin type III repeats in their extracellular domain, modules similar to those found in cell adhesion molecules. Tyro-3 is predominantly localized in the nervous system, with preferential expression in the dendritic compartment of cortical and hippocampal (CA1) pyramidal neurons.

Two structurally related proteins, Gas6 (for growth arrest--specific gene 6) and protein S, induce phosphorylation of Tyro-3 when they bind to its extracellular region. Gas6 can affect proliferation and survival in some cells, but it is not known if it has similar effects in the CNS. We recently found that Gas6 protein and mRNA are widely distributed in the brain in postnatal rats. Gas6 is colocalized with Tyro-3 in specific subsets of neurons, a finding that suggests potential autocrine roles. The results of this localization study strongly suggest that Gas6 is the primary physiologically relevant ligand for Tyro-3 in the nervous system.

So far, no molecules have been detected that interact with Tyro-3 in the neuronal intracellular compartment. We are identifying intracellular targets of Tyro-3 that associate with the receptor under ligand-dependent and ligand-independent conditions and the effects of neural activity in such associations. Identification of these targets is important, because they could provide clues to the cellular functions affected by Tyro-3 and Gas6 in neurons. With these efforts, we hope to uncover the role of the Gas6 and Tyro-3 in molecular mechanisms that underlie important functional processes of the developing and mature nervous system.