Growth arrest specific gene (GAS) 6 modulates platelet thrombus formation and vascular wall homeostasis and represents an attractive drug target.
GAS6, the product of growth arrest specific (GAS) gene 6 is a ligand for the tyrosine protein kinase receptors Axl, Tyro3 and Mer whose signaling has been implicated in cell growth, survival, adhesion and migration. Although a secreted human vitamin K-dependent protein with close structural similarity with protein S, GAS6 does not exhibit anticoagulant properties but rather may be an important regulator of vascular homeostasis and platelet signaling. GAS6 signals via its receptor tyrosine kinases and appears to modulate platelet outside-in signaling via GP alpha(IIb)beta(III), playing a key role in the perpetuation of platelet aggregates and clot retraction. GAS6 is also implicated in foam cell formation and neointimal proliferation in response to vascular injury. Thus GAS6 acts at key points in the pathophysiology of atherosclerosis and thrombosis; two processes implicated in most acute cardiovascular pathology. Inhibition of GAS6 or its receptors may provide antithrombotic activity in the absence of increased bleeding and thus presents an attractive drug target. GAS6 signaling may be modulated through direct antibody inhibition, blockade of its receptors or GAS6 trapping. However, ubiquitous expression of GAS6 and its receptors and the diverse biological effects of the pathway may make selective drug targeting difficult.
Maree
Andrew O
AO
Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. amaree@mgh.harvard.edu
Jneid
Hani
H
Palacios
Igor F
IF
Rosenfield
Kenneth
K
MacRae
Calum A
CA
Fitzgerald
Desmond J
DJ
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology / Q000502:physiology*; D016503:Drug Delivery Systems / Q000379:methods*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000008:administration & dosage; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D013927:Thrombosis / Q000097:blood* / Q000188:drug therapy / Q000209:etiology; D000099255:Growth Arrest-Specific Protein 6
D005343:Fibrinolytic Agents; D036341:Intercellular Signaling Peptides and Proteins; D000099255:Growth Arrest-Specific Protein 6