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 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 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 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 γ-carboxylation of ligands is essential for the full activation of TAMs and that 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 both immunoregulation and the recognition and removal of ACs.
authors: From the Department of Biochemistry and Molecular Biology, University Hospital Cancer Center and Center for Immunity and Inflammation, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103, and.
authors: Wen-I
authors: WI
authors: Tsou
authors: From the Department of Biochemistry and Molecular Biology, University Hospital Cancer Center and.
authors: Khanh-Quynh N
authors: KQ
authors: Nguyen
authors: the Department of Biochemistry and.
authors: Daniel A
authors: DA
authors: Calarese
authors: the Department of Biochemistry and.
authors: Scott J
authors: SJ
authors: Garforth
authors: From the Department of Biochemistry and Molecular Biology, University Hospital Cancer Center and.
authors: Anita L
authors: AL
authors: Antes
authors: From the Department of Biochemistry and Molecular Biology, University Hospital Cancer Center and Center for Immunity and Inflammation, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103, and.
authors: Sergey V
authors: SV
authors: Smirnov
authors: the Department of Biochemistry and Albert Einstein Cancer Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461.
authors: Steve C
authors: SC
authors: Almo
authors: From the Department of Biochemistry and Molecular Biology, University Hospital Cancer Center and birgera@njms.rutgers.edu.
authors: Raymond B
authors: RB
authors: Birge
authors: From the Department of Biochemistry and Molecular Biology, University Hospital Cancer Center and Center for Immunity and Inflammation, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103, and kotenkse@njms.rutgers.edu.
authors: Sergei V
authors: SV
authors: Kotenko
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001798:Blood Proteins / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D019169:Jurkat Cells; D017293:Protein S; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D054243:Vesicular Stomatitis / Q000235:genetics; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D001798:Blood Proteins; D036341:Intercellular Signaling Peptides and Proteins; D017293:Protein S; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C523390:PROS1 protein, human; C097072:MERTK protein, human; C084944:TYRO3 protein, human; C000722289:AXL protein, human
keywords: AXL; Apoptosis; GAS6; MER; Phospholipid; Protein S; Receptor-tyrosine Kinase; Signal Transduction; TYRO3; Virus