BBB Seminar: Björn Dahlbäck
Gas6 and the TAM tyrosine kinase receptor family in apoptotic cell clearance, autoimmunity and renal cell carcinoma
Department of Laboratory Medicine, Lund University, Skåne University
Hospital, Malmö, Sweden
Growth arrest specific protein 6 (Gas6) is a multidomain 75-kDa vitamin K-dependent protein, which is widely expressed. The N-terminal vitamin K-dependent Gla domain binds negatively charged phospholipids, e.g. those that are exposed on apoptotic cells. The C-terminal G-type domains of Gas6 bind and stimulate the TAM tyrosine kinase receptors, which include Tyro3, Axl and Mer. Although the TAM receptors are widely expressed, the three family members have distinct expression patterns. The functional outcomes of the Gas6-mediated activation of the TAM receptors include anti-apoptotic and prosurvival effects, apoptotic cell clearance and in macrophages/dendritic cells, TAM stimulation results in down-regulation of the inflammatory response. Gas6 knockout mice are phenotypically normal, whereas TAM knockouts, in particular when combined, have severe autoimmunity effects and cause defective apoptotic cell clearance. Based on Gas6 knockout studies, Gas6 was proposed to be important for platelet functions mediating autocrine stimulation of platelet-bound Axl. However, Gas6 is undetectable in human platelets but found circulating at subnanomolar concentrations in plasma. This Gas6 is probably functionally inhibited as it is bound in complex with the soluble extra-cellular part of Axl (sAxl), which is shed from cells as a result of proteolytic cleavage. We have developed immune-assays to measure the plasma concentrations of Gas6 and the soluble TAM receptors and have investigated cohorts of patients with different diseases, including autoimmune diseases, sepsis, severe atherosclerosis and renal cell carcinoma. Together these studies demonstrate that Gas6 and sAxl correlate with the acute phase reaction and reflect the severity of all investigated diseases. This was particularly obvious in the sepsis study. The sTyro3 and sMer was studied in rheumatic diseases and it was noteworthy that sMer was particularly high in severe systemic erythematosus (SLE). SLE is characterized by defective clearance of apoptotic cells and in this context it is interesting to note that Mer is important for uptake of apoptotic cells to which Gas6 is bound. In a large cohort of renal cell carcinoma patients, we not only measured plasma concentrations of Gas6 and sAxl but also the Axl protein in the tumours by immunohistochemistry (IHC) and mRNA coding for Axl and Gas6 in the tumour tissue. A noteworthy finding was that cases with the lowest mRNA levels for Axl (≤25th percentile) had much better prognosis than the rest of the cases. However, no correlations were found between the IHC pattern and Axl mRNA, or the IHC and the severity of the tumour. In conclusion, Gas6 and the soluble TAM receptors are found circulating in plasma and their concentrations reflect the severity of several diseases. In renal cell carcinoma we found cases with low Axl mRNA to have longer survival times than those where tumours had a medium or high Axl mRNA content.
Selected recent publications:
Ekman, C., Gottsater, A., Lindblad, B., and Dahlback, B. 2010. Plasma concentrations of Gas6 and soluble Axl correlate with disease and predict mortality in patients with critical limb ischemia. Clin Biochem 43:873-876.
Ekman, C., Linder, A., Akesson, P., and Dahlback, B. 2010. Plasma concentrations of Gas6 (growth arrest specific protein 6) and its soluble tyrosine kinase receptor sAxl in sepsis and systemic inflammatory response syndromes. Crit Care 14:R158.
Ekman, C., Site, D.F., Gottsater, A., Lindblad, B., and Dahlback, B. 2010. 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. Clin Biochem 43:110-114.
Ekman, C., Stenhoff, J., and Dahlback, B. 2010. Gas6 is complexed to the soluble tyrosine kinase receptor Axl in human blood. J Thromb Haemost 8:838-844.
Ekman, C., Jonsen, A., Sturfelt, G., Bengtsson, A.A., and Dahlback, B. 2011. Plasma concentrations of Gas6 and sAxl correlate with disease activity in systemic lupus erythematosus. Rheumatology (Oxford) 50:1064-1069.
Wu, J., Ekman, C., Jonsen, A., Sturfelt, G., Bengtsson, A.A., Gottsater, A., Lindblad, B., Lindqvist, E., Saxne, T., and Dahlback, B. 2011. Increased plasma levels of the soluble Mer tyrosine kinase receptor in systemic lupus erythematosus related to disease activity and nephritis. Arthritis Res Ther 13:R62.
Host: James Lorens, Department of Biomedicine