Apoptotic Cell Recognition Receptors, TYRO3, AXL and MER (TAM), Demonstrate Distinct Patterns and Complex Regulation of Ligand-Induced Activation and Signaling — ASN Events
  1. Schedule
  2. Poster Session 2
  3. Apoptotic Cell Recognition Receptors, TYRO3, AXL and MER (TAM), Demonstrate Distinct Patterns and Complex Regulation of Ligand-Induced Activation and Signaling

Apoptotic Cell Recognition Receptors, TYRO3, AXL and MER (TAM), Demonstrate Distinct Patterns and Complex Regulation of Ligand-Induced Activation and Signaling (#340)

Wen-I Tsou 1 , Khanh-Quynh N Nguyen 1 , Daniel A Calarese 2 , Scott J Garforth 2 , Anita Antes 1 , Sergey V Smirnov 1 , Steve C Almo 2 , Raymond B Birge 1 , Sergei V Kotenko 1
  1. Rutgers, New Jersey Medical School, Newark, NJ, United States
  2. Albert Einstein College of Medicine of Yeshiva University, New York, NY, USA

Efficient recognition and removal of apoptotic cells by phagocytes lead to the active suppression of inflammatory responses and the induction of tolerance. Apoptotic cell (AC) recognition receptors, TYRO3, AXL and MER, share similar structural organization of their extracellular and intracellular domains, and form a subfamily of receptor tyrosine kinases (RTKs), abbreviated as TAMs. Activation of TAMs is triggered by secreted glycoproteins, growth arrest-specific gene 6 (GAS6) or protein S (PROS1), that bind to TAMs through their C-terminal Laminin G (LG) domains. In turn, GAS6 and PROS1 are γ-carboxylated on glutamic acid residues in their N-terminal Gla domains and interact in a Ca2+-dependent manner with externalized phosphatidylserine (PS) on the surface of ACs and enveloped viruses. Therefore, GAS6 and PROS1 act as bridging factors: their γ-carboxylated Gla domains bind to PS and opsonize ACs, whereas their LG domains interact with TAMs, enabling TAMs to bind indirectly to ACs and act as immunoregulatory receptors that dampen inflammation. Although TAMs share significant similarity, very little is known about the specificity of interaction between TAMs and their ligands in the context of apoptotic cells, and about downstream signaling cascades. We generated and utilized a set of reporter cell lines expressing chimeric TAM receptors to demonstrate that each TAM has a unique pattern of interaction with GAS6 and PROS1. These interactions are also differentially affected by the presence of ACs, PS liposomes, and enveloped viruses. We also demonstrated that γ-carboxylation of ligands is essential for the full activation of TAMs. In addition, we found that TAM-mediated signaling up-regulates expression levels of programmed death-ligand 1 (PD-L1) and PD-L2 that play an important role in immunosuppression. Overall, these studies reveal that, despite their similarity, TYRO3, AXL and MER perform distinct but overlapping functions in the recognition and removal of ACs, and in the regulation of inflammatory and immune responses.