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"Receptor Tyrosine Kinases, TYRO3, AXL and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-Induced Activation"

by
Wen-I Tsou
Biochemistry and Molecular Biology Program
B.S. 2002, National Taiwan University, Taiwan
M.S. 2004, National Taiwan University, Taiwan


Thesis Advisor: Sergei V. Kotenko, Ph.D.
Associate Professor
Department of Biochemistry and Molecular Biology

Tuesday, July 1, 2014
10:00 A.M., MSB E-609b


Abstract

TYRO3, AXL and MER receptors (TAMs) are three homologous type I receptor tyrosine kinases that are activated by endogenous ligands, protein S (PROS1) and growth arrest-specific gene 6 (GAS6). These ligands can either activate TAMs as soluble factors, or in turn, opsonize phosphatidylserine (PS) on apoptotic cells (ACs) and serve as bridging molecules between ACs and TAMs. Abnormal expression and activation of TAMs have been implicated in promoting proliferation and survival of cancer cells, as well as in suppressing anti-tumor immunity. Despite the fact that TAM receptors share significant similarity, little is known about the specificity of interaction between TAM receptors and their ligands, particularly in the context of ACs, and about functional diversities of TAM receptors. To study ligand mediated activation of TAMs, we generated a series of reporter cell lines expressing chimeric TAM receptors which allowed us to demonstrate that each TAM receptor has a unique pattern of interaction with and activation by GAS6 and PROS1, which is also differentially affected by the presence of ACs, PS-containing lipid vesicles and enveloped virus. We also demonstrated that g-carboxylation of ligands is essential for the full activation of TAMs and soluble immunoglobulin-like TAM domains act as specific ligand antagonists. These studies demonstrate that despite their similarity, TYRO3, AXL and MER are likely to perform distinct functions in the recognition and removal of ACs, as well as in immunoregulation.


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