title: The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases.
abstract: We report the identification of ligands for Tyro 3 (alternatively called Sky, rse, brt, or tif) and Axl (alternatively, Ark or UFO), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein S, a protease regulator that is a potent anticoagulant, and Gas6, a protein related to protein S but lacking any known function. Our results are reminiscent of recent findings that the procoagulant thrombin, a protease that drives clot formation by cleaving fibrinogen to form fibrin, also binds and activates intracellular signaling via a G protein-coupled cell surface receptor. Proteases and protease regulators that also activate specific cell surface receptors may serve to integrate coagulation with associated cellular responses required for tissue repair and growth, as well as to coordinate protease cascades and associated cellular responses in other systems, such as those involved in growth and remodeling of the nervous system.
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: Trevor N
authors.initials: TN
authors.lastname: Stitt
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Conn
authors.affiliation: Molecular Neurobiology Laboratory The Salk Institute La Jolla, California 92037, USA; Department of Neurosciences University of California, San Diego La Jolla, California 92093, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Goret
authors.affiliation: Department of Neuropharmacology The Scripps Research Institute La Jolla, California 92037, USA.
authors.forename: Cary
authors.initials: C
authors.lastname: Lai
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Bruno
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: Czeslaw
authors.initials: C
authors.lastname: Radzlejewski
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Mattsson
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: John
authors.initials: J
authors.lastname: Fisher
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Gies
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: Pamela F
authors.initials: PF
authors.lastname: Jones
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Masiakowski
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: Terence E
authors.initials: TE
authors.lastname: Ryan
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Tobkes
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Chen
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: DiStefano
authors.affiliation: Department of Biochemistry University of Vermont College of Medicine Burlington, Vermont 05405, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: Long
authors.affiliation: Department of Microbiology and Kaplan Cancer Center New York University School of Medicine New York, New York 10016, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Basilico
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Goldfarb
authors.affiliation: Molecular Neurobiology Laboratory The Salk Institute La Jolla, California 92037, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Lemke
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
authors.affiliation: Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015152:Blotting, Northern; D002455:Cell Division; D002846:Chromatography, Affinity; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017293:Protein S / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D015513:Oncogene Proteins; D017293:Protein S; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C084944:TYRO3 protein, human; C000722290:AXL receptor tyrosine kinase, mouse