Disease relevance of GAS6

• Expression of the growth arrest-specific gene 6 (GAS6) in leukemia and lymphoma cell lines [1].
• The predominantly GAS6-expressing cell lines of non-lymphoid origin have been established from acute myeloid leukemias of the M4 subtype (3/4) [1].
• In order to detect aberrant expression of GAS6 we examined gene expression in 46 cell lines of precursor B-, B- and T-cell origin as well as from Hodgkin's disease and cell lines established from various myeloproliferative disorders [1].
• Coexpression of Gas6/Axl in human ovarian cancers [2].
• Furthermore, GAS6 was also demonstrated to be induced by estrogen in ER positive breast cancer cells [3].

High impact information on GAS6

• Reevaluation of the roles of protein S and Gas6 as ligands for the receptor tyrosine kinase Rse/Tyro 3 [4].
• These findings warrant further evaluation of the possible therapeutic use of Gas6 inhibition for prevention of thrombosis [5].
• Gas6 amplified platelet aggregation and secretion in response to known agonists [5].
• In addition, we found that Gas6 antibodies inhibited platelet aggregation in vitro and protected mice against fatal thrombo embolism without causing bleeding in vivo [5].
• 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 [5].

Chemical compound and disease context of GAS6

• Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in pediatric thyroid carcinomas around chernobyl [6].
• Furthermore, "trapping" Gas6 prevents pathological thrombosis, which indicates that blocking this novel cross-talk between the Gas6-Rs and alpha(IIb)beta(3) integrin may constitute a novel target for antithrombotic therapy [7].
• 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 [5].
• Moreover, in a mouse model of thrombosis, administration of Gas6 or Sky blocking antibodies resulted in a decrease in thrombus weight similar to clopidogrel but, unlike clopidogrel, produced no increase in template bleeding [8].
• To test whether stimulation of Axl can enhance survival of uveal melanoma cells, we assessed the degree of mitogenesis and cell survival by bromodeoxyuridine incorporation and trypan blue exclusion, respectively, upon stimulation of Mel 290 uveal melanoma cells with Gas6 in vitro [9].

Biological context of GAS6

• Assignment of the human GAS6 gene to chromosome 13q34 by fluorescence in situ hybridization [10].
• The initial identification of GAS6 as a protein expressed in response to growth arrest suggested that it might function as a negative regulator of cell proliferation [1].
• In our study, the expression of GAS6 reveals a constitutive transcriptional activation in 8/46 cases of proliferating cell lines [1].
• Although a general mechanism seems most unlikely, further studies are necessary to demonstrate the involvement of GAS6 in single cases of disordered growth or chemotaxis/adhesion of leukemia and lymphomas [1].
• SSCP analysis of PCR-amplified GAS6 exons with their intron-flanking regions from a minimum of 12 control DNA samples, revealed the presence of eight different variants, which were confirmed to be single nucleotide polymorphisms (SNPs) [11].

Anatomical context of GAS6

• Here, we show that Axl stimulation by GAS6 results in inhibition of the ligand-dependent activation of vascular endothelial growth factor (VEGF) receptor 2 and the consequent activation of an angiogenic program in vascular endothelial cells [12].
• GAS6 and Axl are both expressed in endothelial cells, where they are involved in many processes such as leukocyte transmigration through capillaries and neointima formation in injured vessels [12].
• Interestingly, the steady state mRNA levels showed neglectable GAS6 expression in precursor B and B-cell lines (1/9), but could be detected in terminally differentiated plasma cell lines (4/4) [1].
• The GAS6 mRNA expression could be shown in 4/22 cell lines of the lymphoid arm and in 4/17 of the myeloid lineages of the hematopoietic system [1].
• It is suggested that Gas6 and Axl signal transduction is aberrantly stimulated in endometriotic endometria, and is plausibly related to its growth potential [13].

Associations of GAS6 with chemical compounds

• GAS6, the product of a growth arrest specific (GAS) gene, is the ligand of the tyrosine kinase receptor Axl [12].
• Analysis of localization of GAS6 by confocal microscopy and cytofluorimetric analysis showed that it is concentrated along the plasma membrane in resting EC and treatment with PAF induces depletion and/or redistribution of the molecule [14].
• These results suggested that GAS6 is an estrogen target gene in mammary epithelial cells [3].
• A significant decrease in CNP+/TUNEL+ oligodendrocytes was observed when recombinant human Gas6 (rhGas6) was administered to oligodendrocytes plated on poly-L-lysine, supporting a role for Gas6 signaling in oligodendrocyte survival during a period of active myelination in human fetal spinal cord development [15].
• Paracrine agonists such as ADP, thromboxane, and Gas6 are required for platelet aggregate formation [16].

Regulatory relationships of GAS6

• Gas6 has previously been shown to activate both Axl and Rse/Tyro3, two other receptor tyrosine kinases in the same family as Mer [17].
• C-mer is a receptor tyrosine kinase activated by the ligand Gas6 [18].

Other interactions of GAS6

• In order to demonstrate evidence for an autocrine regulation of growth in permanent hematopoietic cell lines, we measured the GAS6 expression in cell lines with strong positivity for the AXL/UFO receptor mRNA [1].
• Only the minor Gas6 binding site is highly conserved in the other Axl family receptors, Sky/Tyro3 and Mer [19].
• Protein S and a structurally similar protein, Gas6, have been found to stimulate members of the Axl/Sky family of receptor tyrosine kinases [20].
• Assignments of the GAS6, POSTN and EFNB2 genes to SSC11 by somatic cell and radiation hybrid panels [21].
• One of the most interesting aspects of this hypothetical protein is that its Gla domain is highly homologous to the Gla domain of Gas6, a ligand for Axl, while its receptor tyrosine kinase domain is highly homologous to Axl [22].

Analytical, diagnostic and therapeutic context of GAS6

• METHODS: In ovarian cancers of 90 cases, the histoscores and mRNA levels of Gas6, Axl and Sky were determined by immunohistochemistry and competitive reverse transcription-polymerase chain reaction-Southern blot analysis using the recombinant RNA, respectively [2].
• Titration experiments showed that high concentrations of GAS6 were needed to inhibit PMN adhesion and that inhibition was dose-dependent at the concentration range of 0.1 to 1 microg/mL [14].
• Electrophoretic mobility shift assay revealed that ERalpha interacted with the ERE in the GAS6 promoter [3].
• Chromatin immunoprecipitation demonstrated that ERalpha was recruited to the GAS6 promoter upon estrogen stimulation [3].
• The apparent relative association and dissociation rate constants of Gas6 for soluble Axl, Rse/Tyro3 and Mer were compared using surface plasmon resonance [17].

References