Abstract
The TAM receptor tyrosine kinases Tyro3, Axl, and Mer regulate key features of cellular physiology, yet the differential activities of the TAM ligands Gas6 and Protein S are poorly understood. We have used biochemical and genetic analyses to delineate the rules for TAM receptor-ligand engagement and find that the TAMs segregate into two groups based on ligand specificity, regulation by phosphatidylserine, and function. Tyro3 and Mer are activated by both ligands but only Gas6 activates Axl. Optimal TAM signaling requires coincident TAM ligand engagement of both its receptor and the phospholipid phosphatidylserine (PtdSer): Gas6 lacking its PtdSer-binding 'Gla domain' is significantly weakened as a Tyro3/Mer agonist and is inert as an Axl agonist, even though it binds to Axl with wild-type affinity. In two settings of TAM-dependent homeostatic phagocytosis, Mer plays a predominant role while Axl is dispensable, and activation of Mer by Protein S is sufficient to drive phagocytosis.
Highlights
The three receptor tyrosine kinases of the TAM family–Tyro3, Axl, and Mer—are expressed in sentinel cells of the immune system, endothelial cells of the vasculature, neurons and glia of the nervous system, and professional phagocytes of the immune, nervous, and reproductive systems (Lemke, 2013)
Size exclusion chromatography suggested that full-length Gas6 in solution is a mixture of monomers, dimers, and/or higher order multimers, whereas the Gla-less form appeared as a monomer (Figure 1—figure supplement 1). These elution profiles are consistent with earlier work on hPros1, indicating that it forms disulfide-linked multimers, and that multimerization is enhanced by apoptotic cells (Uehara and Shacter, 2008)
We found that a Tyro3–Axl chimeric receptor composed of the Tyro3 extracellular domain linked to the Axl tyrosine kinase, when expressed in TAM TKO mouse embryo fibroblast (MEF), displayed diminished activation by Gla-less Gas6 similar to that seen with Tyro3 (Figure 3A,D)
Summary
The three receptor tyrosine kinases of the TAM family–Tyro, Axl, and Mer—are expressed in sentinel cells of the immune system, endothelial cells of the vasculature, neurons and glia of the nervous system, and professional phagocytes of the immune, nervous, and reproductive systems (Lemke, 2013). In these settings, TAM signaling regulates multiple functions but two are especially prominent. Elevated TAM expression has recently been implicated in increased susceptibility to infection by enveloped viruses (Shimojima et al, 2006; Morizono et al, 2011; Meertens et al, 2012; Bhattacharyya et al, 2013)
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