The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases.
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.
Stitt
Trevor N
TN
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Conn
Greg
G
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Goret
Martin
M
Molecular Neurobiology Laboratory The Salk Institute La Jolla, California 92037, USA; Department of Neurosciences University of California, San Diego La Jolla, California 92093, USA.
Lai
Cary
C
Department of Neuropharmacology The Scripps Research Institute La Jolla, California 92037, USA.
Bruno
Joanne
J
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Radzlejewski
Czeslaw
C
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Mattsson
Karen
K
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Fisher
John
J
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Gies
David R
DR
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Jones
Pamela F
PF
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Masiakowski
Piotr
P
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Ryan
Terence E
TE
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Tobkes
Nancy J
NJ
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Chen
D H
DH
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
DiStefano
Peter S
PS
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Long
George L
GL
Department of Biochemistry University of Vermont College of Medicine Burlington, Vermont 05405, USA.
Basilico
Claudio
C
Department of Microbiology and Kaplan Cancer Center New York University School of Medicine New York, New York 10016, USA.
Goldfarb
Mitchell P
MP
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Lemke
Greg
G
Molecular Neurobiology Laboratory The Salk Institute La Jolla, California 92037, USA.
Glass
David J
DJ
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
Yancopoulos
George D
GD
Regeneron Pharmaceuticals, Incorporated 777 Old Saw Mill River Road Tarrytown, New York 10591, USA.
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
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