title: Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities.
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.
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Erin D
authors.initials: ED
authors.lastname: Lew
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Oh
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Burrola
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, United States.
authors.forename: Irit
authors.initials: I
authors.lastname: Lax
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Zagórska
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Paqui G
authors.identifier: http://orcid.org/0000-0001-5749-8426
authors.initials: PG
authors.lastname: Través
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, United States.
authors.forename: Greg
authors.initials: G
authors.lastname: Lemke
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004622:Embryo, Mammalian; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000235:genetics; D010718:Phosphatidylserines / Q000378:metabolism* / Q000494:pharmacology; D061251:Primary Cell Culture; D017293:Protein S / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010718:Phosphatidylserines; D017293:Protein S; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C490767:Mertk protein, mouse; C513478:Tyro3 protein, mouse
keywords: Axl; Gas6; Mertk; Pros1; Tyro3; biochemistry; immunology; mouse; receptor tyrosine kinase