Receptor tyrosine kinases, TYRO3, AXL, and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation

Wen I. Tsou, Khanh Quynh N. Nguyen, Daniel A. Calarese, Scott J. Garforth, Anita L. Antes, Sergey V. Smirnov, Steve C. Almo, Raymond Birge, Sergei Kotenko

Research output: Contribution to journalArticle

67 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)25750-25763
Number of pages14
JournalJournal of Biological Chemistry
Volume289
Issue number37
DOIs
StatePublished - Sep 12 2014

Fingerprint

Receptor Protein-Tyrosine Kinases
Chemical activation
Ligands
Cells
Genes
Carboxylation
Phosphatidylserines
Protein S
Growth
Viruses
Immunoglobulins
Tumors
Immunity
Neoplasms
Cell Survival
Lipids
Cell Line
Molecules

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Tsou, Wen I. ; Nguyen, Khanh Quynh N. ; Calarese, Daniel A. ; Garforth, Scott J. ; Antes, Anita L. ; Smirnov, Sergey V. ; Almo, Steve C. ; Birge, Raymond ; Kotenko, Sergei. / Receptor tyrosine kinases, TYRO3, AXL, and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 37. pp. 25750-25763.
@article{5886754a612842babe591eaa5a6f8e5a,
title = "Receptor tyrosine kinases, TYRO3, AXL, and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation",
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 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.",
author = "Tsou, {Wen I.} and Nguyen, {Khanh Quynh N.} and Calarese, {Daniel A.} and Garforth, {Scott J.} and Antes, {Anita L.} and Smirnov, {Sergey V.} and Almo, {Steve C.} and Raymond Birge and Sergei Kotenko",
year = "2014",
month = "9",
day = "12",
doi = "10.1074/jbc.M114.569020",
language = "English (US)",
volume = "289",
pages = "25750--25763",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "37",

}

Receptor tyrosine kinases, TYRO3, AXL, and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation. / Tsou, Wen I.; Nguyen, Khanh Quynh N.; Calarese, Daniel A.; Garforth, Scott J.; Antes, Anita L.; Smirnov, Sergey V.; Almo, Steve C.; Birge, Raymond; Kotenko, Sergei.

In: Journal of Biological Chemistry, Vol. 289, No. 37, 12.09.2014, p. 25750-25763.

Research output: Contribution to journalArticle

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

AU - Kotenko, Sergei

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.

UR - http://www.scopus.com/inward/record.url?scp=84907164891&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907164891&partnerID=8YFLogxK

U2 - 10.1074/jbc.M114.569020

DO - 10.1074/jbc.M114.569020

M3 - Article

VL - 289

SP - 25750

EP - 25763

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 37

ER -