TY - JOUR
T1 - Receptor tyrosine kinases, TYRO3, AXL, and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation
AU - Tsou, Wen I.
AU - Nguyen, Khanh Quynh N.
AU - Calarese, Daniel A.
AU - Garforth, Scott J.
AU - Antes, Anita L.
AU - Smirnov, Sergey V.
AU - Almo, Steve C.
AU - Birge, Raymond B.
AU - Kotenko, Sergei V.
N1 - Publisher Copyright:
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2014/9/12
Y1 - 2014/9/12
N2 - 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 thatTAMreceptors share significant similarity, little is known about the specificity of interaction betweenTAM receptors and their ligands, particularly in the context of ACs, and about the functional diversity of TAM receptors. To study ligand-mediated activation of TAMs, we generated a series of reporter cell lines expressing chimeric TAM receptors. Using this system, we found that eachTAMreceptor has a unique pattern of interaction with and activation by GAS6 and PROS1, which is also differentially affected by the presence of ACs, PScontaining lipid vesicles and enveloped virus. We also demonstrated that γ-carboxylation of ligands is essential for the full activation ofTAMsand that soluble immunoglobulin-likeTAM domains act as specific ligand antagonists. These studies demonstrate that, despite their similarity, TYRO3, AXL, and MER are likely to perform distinct functions in both immunoregulation and the recognition and removal of ACs.
AB - 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 thatTAMreceptors share significant similarity, little is known about the specificity of interaction betweenTAM receptors and their ligands, particularly in the context of ACs, and about the functional diversity of TAM receptors. To study ligand-mediated activation of TAMs, we generated a series of reporter cell lines expressing chimeric TAM receptors. Using this system, we found that eachTAMreceptor has a unique pattern of interaction with and activation by GAS6 and PROS1, which is also differentially affected by the presence of ACs, PScontaining lipid vesicles and enveloped virus. We also demonstrated that γ-carboxylation of ligands is essential for the full activation ofTAMsand that soluble immunoglobulin-likeTAM domains act as specific ligand antagonists. These studies demonstrate that, despite their similarity, TYRO3, AXL, and MER are likely to perform distinct functions in both immunoregulation and the recognition and removal of ACs.
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U2 - 10.1074/jbc.M114.569020
DO - 10.1074/jbc.M114.569020
M3 - Article
C2 - 25074926
AN - SCOPUS:84907164891
SN - 0021-9258
VL - 289
SP - 25750
EP - 25763
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -