The Soluble Form of the Axl Receptor Tyrosine Kinase

Abstract: The present investigation focus on the receptor Axl, which is a member of the receptor tyrosine kinase family. Axl is activated by the ligand Gas6 inducing cell growth and proliferation, but also regulate inflammation and vascular homeostasis. The Axl receptor can be cleaved outside the membrane, releasing the extracellular, soluble domain, which alone can bind Gas6, removing it from cellbound receptors. The first study focus on soluble Axl (sAxl), which is found to be secreted from several human cell lines and is present in human serum and plasma. An ELISA is developed against Axl to determine the concentration of sAxl in human circulation. Through immunoprecipitation and gel filtration, Gas6 is found to be in complex with sAxl, with sAxl present in excess of Gas6. In the second study, a number of patients with abdominal aortic aneurysms are investigated with Gas6 and sAxl ELISAs to widen our understanding of the Gas6-Axl system. In the patients, Gas6 is increased and sAxl is decreased in the patient group. Aneurysm size correlated to Gas6 concentration and inversly to sAxl concentration. The Gas6/sAxl ratio correlated even better to Aneurysm size, and 40% of all patients with large Aneurysms had higher Gas6/sAxl ratio than any in the control group. The third study investigated patients with critical limb ischemia. The patients had high Gas6 and sAxl, and both proteins correlated with several inflammatory markers. Patients with high Gas6 and sAxl had poorer prognosis with higher mortality, independent of age and gender. The fourth study assesed patients with Sepsis and related inflammatory conditions. In septic patients, Gas6 was twice the concentration observed in the controls, and sAxl was also increased. Gas6 was especially increased in patients with organ failure, patients demanding intensive care and renal support. The fifth study focused on patients with systemic lupus erythematosus, and in this material Gas6 and sAxl correlated with the disease index in those patients. Gas6 and sAxl was markedly increased in patients with glomerulonephritis and presence of anti-DNA antibodies. Altogether, the results from this thesis include that Gas6 is bound to sAxl in circulation and that Gas6 and sAxl are increased in inflammatory conditions.