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- Ekman, Carl, et al.
(författare)
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Gas6 is complexed to soluble tyrosine kinase receptor Axl in human blood.
- 2010
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 8:4, s. 838-844
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Tidskriftsartikel (refereegranskat)abstract
- Summary Background: The vitamin K-dependent Gas6 protein (product of growth arrest specific gene 6) binds to, and activates the TAM receptor tyrosine kinases Tyro3, Axl, and Mer. Gas6 and the TAM receptors have been suggested to be important for primary platelet functions, but Gas6 cannot be found in human platelets. However, Gas6 is present in human plasma at a concentration of around 0.2 nM, which is 1,000-fold lower than that of the homologous protein S. The Axl and Mer receptors can be cleaved close to the cell membrane, yielding soluble molecules consisting of the extracellular parts of the receptors. Objective: To investigate if soluble Axl (sAxl) is present in human serum and plasma and if Gas6 circulates in complex with sAxl. Methods: We expressed recombinant sAxl, raised antibodies, developed and validated an ELISA for Axl. Serum and plasma were analyzed using ELISAs for Gas6, Axl, and sAxl-Gas6 complexes. Serum was gel filtered and fractions analyzed by the different ELISAs to determine if Gas6 in serum is free or complexed. Immunoprecipitation was used to investigate binding between Gas6 and sAxl in serum. Results: sAxl is present in serum and plasma at around 0.6 nM and all Gas6 is bound to sAxl. No complexes between Gas6 and the soluble forms of Mer and Tyro3 could be detected, indicating that sAxl is the physiological binder of Gas6 in human serum. Conclusions: Gas6 in circulation is bound to sAxl suggesting circulating Gas6 to be inhibited and incapable of stimulating the TAM receptors.
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| 2. |
- Ekman, Carl, et al.
(författare)
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Plasma concentrations of Gas6 and sAxl correlate with disease activity in systemic lupus erythematosus.
- 2011
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 50, s. 1064-1069
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. SLE is a systemic autoimmune disease with an annual incidence of 3.8 per 100 000. Several pathogenic mechanisms are believed to be operating in SLE, including an impaired clearance of apoptotic cells, activation of the type I IFN pathway and generation of autoimmune leucocytes. Growth arrest-specific protein 6 (Gas6) and its receptor Axl are known to regulate inflammation and may be implicated in lupus pathogenesis. We have recently developed immunological methods to quantify the vitamin-K-dependent protein Gas6 and its soluble receptor sAxl in human plasma, which we have used to investigate the role of Gas6 and soluble Axl in SLE. Methods. We have investigated the relation between the plasma concentrations of Gas6 and sAxl and disease activity and specific symptoms in 96 SLE patients. Results. Gas6 and sAxl concentrations correlated with SLEDAI (r = 0.48, P < 0.001 and r = 0.39, P < 0.001, respectively). Furthermore, concentrations of Gas6 and sAxl correlated with ESR and CRP and inversely with haemoglobin levels. Gas6 and sAxl concentrations were significantly higher in patients with anti-DNA antibodies, leucopenia and GN. Conclusion. The plasma concentrations of Gas6 and sAxl vary with disease activity in SLE, in particular GN, and may have a role in lupus pathogenesis. Furthermore, Gas6 and sAxl may be of use as biomarkers of disease activity.
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| 3. |
- Ekman, Carl, et al.
(författare)
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Plasma concentrations of Gas6 and soluble Axl correlate with disease and predict mortality in patients with critical limb ischemia.
- 2010
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Ingår i: Clinical Biochemistry. - : Elsevier BV. - 1873-2933 .- 0009-9120. ; May 4, s. 873-876
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Critical limb ischemia (CLI) is a severe peripheral arterial disease, characterized by rest pain, ulcers and gangrene in the legs. Gas6 is a vitamin K-dependent protein, which binds and activates the tyrosine kinase receptor Axl. Gas6-mediated Axl-signaling influences endothelial activation, neointima formation and immune regulation. Axl can be cleaved and soluble Axl (sAxl) is detectable in circulation. DESIGN AND METHODS: We quantified plasma concentrations of Gas6 and sAxl in 189 CLI patients and 204 controls. RESULTS: Gas6 and sAxl concentrations were increased in the CLI patients (p<0.0001) and correlated to C-reactive protein, interleukin-6, tumor necrosis factor alpha and neopterin. Patients who died within three years of sampling (n=84) had increased concentrations of Gas6 and sAxl as compared to survivors (p=0.0009 and p=0.0011). CONCLUSIONS: Plasma concentrations of Gas6 and sAxl correlate to inflammation and predict survival. This indicates that Gas6 and sAxl have a role in CLI, presumably connected to the inflammatory process.
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| 4. |
- Ekman, Carl, et al.
(författare)
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Plasma concentrations of Gas6 (growth arrest specific protein 6) and its soluble tyrosine kinase receptor sAxl in sepsis and systemic inflammatory response syndromes
- 2010
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Ingår i: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Gas6, the protein product of the growth arrest specific gene 6, is present in human circulation at subnanomolar concentrations. It is secreted by endothelial cells and is important for the activation of endothelium during inflammation. Axl, the tyrosine kinase receptor for Gas6, is also present in endothelium and can be cleaved and released into the circulation. The soluble of form Axl (sAxl), which is present in plasma, can bind Gas6 and inhibit Axl-mediated cell signalling. Methods: We have developed reproducible and accurate enzyme-linked immunosorbent assays for both Gas6 and sAxl and used them to investigate plasma samples from 70 patients with severe sepsis, 99 patients with sepsis, 42 patients with various infections causing fever but no systemic inflammatory response syndrome (SIRS), 20 patients with SIRS without verified infection, and 100 blood donors that served as controls. Correlations between Gas6 and sAxl concentrations and other commonly used analytes were investigated. Results: The patients with severe sepsis, sepsis, infection or SIRS had all increased concentrations of Gas6, approximately double compared to what was found in the controls. The concentrations of sAxl were also increased in the patient groups compared to the controls. Gas6 correlated with C-reactive protein, procalcitonin and interleukin 6, whereas sAxl correlated to bilirubin and procalcitonin. Conclusions: We can confirm results of earlier studies showing that circulating Gas6 is increased in sepsis and related syndromes. sAxl is increased, but less pronounced than Gas6. The concentrations of Gas6 and sAxl correlate with a number of inflammatory markers, suggesting a role in systemic inflammation.
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| 5. |
- Ekman, Carl, et al.
(författare)
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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.
- 2010
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Ingår i: Clinical Biochemistry. - : Elsevier BV. - 1873-2933 .- 0009-9120. ; 43, s. 110-114
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The tyrosine kinase receptor Axl is expressed in the vasculature and Gas6 is the ligand. The extracellular part of Axl (sAxl) can be found in circulation. The aim of this study was to determine plasma concentrations of Gas6 and sAxl in patients with abdominal aortic aneurysms (AAA) and to evaluate if Gas6 and sAxl can be used as biomarkers. DESIGN AND METHODS: Immunoassays for sAxl and Gas6 were used to investigate plasma from AAA patients. Patients with large (n=123) or small AAA (n=122) were compared with healthy controls (n=141). RESULTS: Gas6 correlated positively and sAxl correlated negatively with AAA size. As a consequence, the calculated Gas6/sAxl ratios correlated even better to AAA size. Forty percent of all patients with a large AAA had higher Gas6/sAxl ratio than any in the control group. DISCUSSION: The Gas6/Axl system might be involved in AAA pathogenesis, and the Gas6/sAxl ratio may be useful as a biomarker.
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| 6. |
- Gustafsson, Anna, et al.
(författare)
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Differential expression of Axl and Gas6 in renal cell carcinoma reflecting tumor advancement and survival
- 2009
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Ingår i: Clinical Cancer Research. - : American association for cancer research. - 1078-0432 .- 1557-3265. ; 15:14, s. 4742-4749
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Overexpression of the receptor tyrosine kinase Axl is implicated in several cancers. Therefore, we conducted this study to determine the expression of Axl and its ligand Gas6 in various renal cell carcinoma (RCC) types and in oncocytoma. EXPERIMENTAL DESIGN: Real-time quantitative reverse transcription-PCR was used to quantify tumor mRNA levels for Axl and Gas6 in a cohort (n = 221) of RCC patients. Serum levels of soluble sAxl and Gas6 proteins were measured using specific ELISA assays (n = 282). The presence of Axl protein in tumor tissue was evaluated by immunohistochemistry (n = 294). Results were correlated to tumor-associated variables, clinical biochemical tests, and patient survival. RESULTS: Tumor Axl mRNA levels correlated independently to survival when assessed against tumor stage and grade. In the study group, the median cancer-specific survival of all RCC patients during 307 months of follow-up was 55 months (confidence interval, +/-40.4). The 25% of patients with lowest tumor Axl mRNA levels had significantly better survival than the rest (P = 0.0005), with 70% of the patients still alive at the end of follow-up. In contrast, in patients with medium-high Axl mRNA, only 25% were alive at the end of follow-up. Tumor Gas6 mRNA levels correlated to survival, tumor-associated variables, and disease severity as did serum levels of soluble sAxl and Gas6 protein. However, no correlation between Axl protein in tumor tissue and survival was found. CONCLUSIONS: Axl and Gas6 expression in RCC are associated with tumor advancement and patient survival. In particular, low tumor Axl mRNA levels independently correlated with improved survival.
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| 8. |
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| 9. |
- Wu, Jun John, et al.
(författare)
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Increased plasma levels of the soluble Mer tyrosine kinase receptor in systemic lupus erythematosus relate to disease activity and nephritis
- 2011
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Mer and Tyro3 are receptor tyrosine kinases important for the phagocytosis of apoptotic cells. Together with Axl, they constitute the TAM receptor family. These receptors can be shed from the cell membrane and their soluble extracellular regions can be found in plasma. The objective of this study was to elucidate whether the plasma levels of soluble Mer (sMer) and Tyro3 (sTyro3) were increased in systemic lupus erythematosis (SLE), rheumatoid arthritis (RA), or critical limb ischemia (CLI). Methods: ELISA kits were used to test plasma concentrations in controls and in patients with SLE, RA or CLI. Results: Increased levels of, in particular, sMer and, to some extent, sTyro3, were found in patients with SLE or RA, but not in patients with CLI. Patients with SLE demonstrated the highest sMer levels and there was a strong correlation to higher SLE disease activity score (SLEDAI). In contrast, in patients with RA, the sMer levels did not correlate with the disease activity score (DAS). In SLE, sMer levels were particularly high in those with lupus nephritis, patients who also had decreased C1q levels and increased titers of anti-DNA antibodies. After therapy, the plasma concentrations of sMer decreased in parallel to the decrease in SLEDAI score. Conclusions: The plasma concentrations of sMer and sTyro3 were significantly increased in patients with active SLE and RA, suggesting the TAM receptor shedding was affected by these autoimmune diseases. In particular, sMer was increased in SLE, the plasma levels of sMer reflecting disease activity.
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