Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis

Abstract

The growth arrest-specific gene 6 product (Gas6) is a secreted protein related to the anticoagulant protein S but its role in hemostasis is unknown. Here we show that inactivation of the Gas6 gene prevented venous and arterial thrombosis in mice, and protected against fatal collagen/epinephrine-induced thrombo embolism. Gas6-/- mice did not, however, suffer spontaneous bleeding and had normal bleeding after tail clipping. In addition, we found that Gas6 antibodies inhibited platelet aggregation in vitro and protected mice against fatal thrombo embolism without causing bleeding in vivo. Gas6 amplified platelet aggregation and secretion in response to known agonists. Platelet dysfunction in Gas6-/- mice resembled that of patients with platelet signaling transduction defects. Thus, Gas6 is a platelet-response amplifier that plays a significant role in thrombosis. These findings warrant further evaluation of the possible therapeutic use of Gas6 inhibition for prevention of thrombosis.

Immunobiology of the TAM receptors

“…Each protein has a ~60 amino-acid Gla domain at its amino terminus, a region rich in glutamic 19 , genuine insights into the biological roles of these receptors were only obtained when mice lacking TYRO3, AXL, MER or GAS6 were generated and analysed [20][21][22][23][24][25] .…”

“…In contrast to most other receptor PTKs, expression of the TAMs is substantially upregulated postnatally, and is maintained at relatively high levels in adult tissues. Although cDNAs encoding the TAM receptors have been cloned repeatedly from tumour cells, and TAM receptors, particularly AXL, have been implicated in cancer progression 19 , genuine insights into the biological roles of these receptors were only obtained when mice lacking TYRO3, AXL, MER or GAS6 were generated and analysed [20][21][22][23][24][25] .…”

“…In addition to the roles discussed in this Review, TAM receptor signalling has been shown have important regulatory roles in vascular smooth-muscle homeostasis [92][93][94] , in platelet function and thrombus stabilization 23,95,96 , in erythropoiesis 97 and in cancer development and progression 19,98,99 . TAM receptors are also implicated in the regulation of osteoclast function 100,101 , in the control of oligodendrocyte cell survival 102,103 , and in the infection of dendritic cells and other cells by Ebola and Marburg viruses 104,105 .…”

Ligand Recognition and Homophilic Interactions in Tyro3

“…However, it is not clear whether Gas6 is the only ligand for these receptors because, unexpectedly, the main phenotype of Gas6 knock-out mice is different from the phenotypes of the receptor-deficient mice. Gas6 knock-out mice are protected against thrombosis because of a platelet aggregation defect (28). It is also possible that additional mechanisms exist by which the Axl/Tyro3 re-ceptors function, and these mechanisms might not involve signaling through activation of the tyrosine kinase activity but rather cell adhesion processes (29).…”

Plasma concentrations of growth arrest specific protein 6 and the soluble form of its tyrosine kinase receptor Axl as markers of large abdominal aortic aneurysms

“…Gas6 -/-mice are found to be resistant to both arterial and venous thrombosis models 29,30 . Similar results were obtained with Axl/Tyro3/Mer -/-mice 31 .…”