Abstract
The vitamin K-dependent factors protein S (PROS1) and growth-arrest-specific gene 6 (GAS6) and their tyrosine kinase receptors TYRO3, AXL, and MERTK, the TAM subfamily of receptor tyrosine kinases (RTK), are key regulators of inflammation and vascular response to damage. TAM signaling, which has largely studied in the immune system and in cancer, has been involved in coagulation-related pathologies. Because of these established biological functions, the GAS6-PROS1/TAM system is postulated to play an important role in SARS-CoV-2 infection and progression complications. The participation of the TAM system in vascular function and pathology has been previously reported. However, in the context of COVID-19, the role of TAMs could provide new clues in virus-host interplay with important consequences in the way that we understand this pathology. From the viral mimicry used by SARS-CoV-2 to infect cells, to the immunothrombosis that is associated with respiratory failure in COVID-19 patients, TAM signaling seems to be involved at different stages of the disease. TAM targeting is becoming an interesting biomedical strategy, which is useful for COVID-19 treatment now, but also for other viral and inflammatory diseases in the future.
Highlights
TAM receptors (TYRO3, AXL, and MERTK) are a subfamily of receptor tyrosine kinases (RTKs).Being first cloned in 1991 based on RTK domain’s homology [1], no homolog proteins are found in Caenorhabditis elegans or Drosophila melanogaster as TAMs appear late in evolution [2]
Different specificities have been defined for TAM ligands: growth-arrest-specific 6 (GAS6) binds all TAM receptors with higher affinity for AXL [7,8,9], while PROS1 principally engages MERTK and TYRO3, and only in specific cases has been suggested to activate AXL [10]
Ligand binding to Ig-like domains of TAM receptors triggers receptor dimerization, autophosphorylation of intracellular tyrosine, and signal transduction through different pathways, such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase–AKT
Summary
TAM receptors (TYRO3, AXL, and MERTK) are a subfamily of receptor tyrosine kinases (RTKs). The γ-carboxylation of glutamate residues, a process that is dependent on vitamin K, enables the interaction of the Gla-domain with membrane-exposed PtdSer. Different specificities have been defined for TAM ligands: GAS6 binds all TAM receptors with higher affinity for AXL [7,8,9], while PROS1 principally engages MERTK and TYRO3, and only in specific cases has been suggested to activate AXL [10]. Ligand binding to Ig-like domains of TAM receptors triggers receptor dimerization, autophosphorylation of intracellular tyrosine, and signal transduction through different pathways, such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase–AKT (PI3K/AKT), or Janus kinase/signal transducers and activators of transcription (JAK/STAT) [11,12]. Proteolytic cleavage of MERTK and AXL (and possibly TYRO3) by the disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and 17 (ADAM17) efficiently shuts down TAM activity [17,18]
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