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1 From the Lady Davis Institute for Medical Research and The Division of Hematology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada
2 Amgen Corporation, Thousand Oaks, California, USA
* To whom correspondence should be addressed. E-mail: mark.blostein{at}mcgill.ca.
Gas6 is a gamma-carboxylated ligand for the receptor tyrosine kinase Axl. Gas6-Axl interactions can rescue endothelial cells from apoptosis and this study will examine the intracellular signalling mechanisms responsible for this phenomenon. Using flow cytometry, we first confirm that gas6 can abrogate apoptosis induced by serum starvation
of primary cultures of human umbilical vein endothelial cells (HUVECs). This effect is mediated through phosphorylation of the serine-threonine kinase Akt, with maximal phosphorylation observed after 4 hours of treatment with 100 ng/ml gas6. Inhibition of Akt phosphorylation and abrogation of gas6-mediated survival of HUVECs by
Wortmannin implicate phosphoinositide-3 kinase as the mediator of Akt phosphorylation. Dominant negative Akt constructs largely abrogate the protective effect of gas6 on
HUVECs, underscoring the importance of Akt activation in gas6-mediated survival. Several downstream regulators of this survival pathway were identified in HUVECs, namely NF-
as well as the anti-apoptotic and pro-apoptotic proteins, Bcl-2 and caspase 3, respectively. We show that NF- is phosphorylated early after gas6
treatment as evidenced by doublet formation on Western blotting. As well, the level of Bcl-2 protein increases supporting the notion that the Bcl-2 anti-apoptotic pathway is stimulated. The levels of expression of the caspase 3 activation products, p12 and p20, decrease with gas6 treatment consistent with a reduction in pro-apoptotic caspase 3 activation. Taken together, these experiments provide new information about the mechanism underlying gas6 protection from apoptosis in primary endothelial cell
cultures.
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