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Published online before print July 1, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1207829

Received for publication December 13, 2007.
Revised April 29, 2008.
Accepted for publication June 9, 2008.

Article

Signaling through ephrin-A ligand leads to activation of Src-family kinases, Akt phosphorylation, and inhibition of antigen receptor-induced apoptosis

Halvor L. Holen ^*, Mohsen Shadidi , Kristina Narvhus ^*, Oddveig Kjøsnes , Anne Tierens , and Hans-Christian Aasheim ^*@

Departments of Immunology and Pathology, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway; and *Department of Medical Genetics, Ullevaal University Hospital, Oslo, Norway

^@ To whom correspondence should be addressed. E-mail: hansas{at}ulrik.uio.no.

	Abstract

Eph receptor tyrosine kinases and ephrins play important roles in diverse biological processes such as migration, adhesion, and angiogenesis. Forward and reverse signaling has been reported in receptor- and ligand-bearing cells. The ligands can be divided into the transmembrane ephrin-B family and the GPI-anchored ephrin-A family. Here, we show expression of ephrin-A ligands on CD4+ T cells cultured in medium with human serum and the T cell line Jurkat TAg and on cells isolated from patients with T cell lymphomas and T cell leukemias. Functional role and identification of proteins involved in ephrin-A signaling were investigated here in the T cell line Jurkat TAg. Signaling through ephrin-A induces phosphorylation of several proteins, including the Src kinases Lck and Fyn. In addition, PI-3K is activated, shown by induced phosphorylation of the Akt kinase. An ephrin-A signaling complex could be isolated, containing several phosphorylated proteins including Lck and Fyn. Interestingly, we show that signaling through ephrin-A in Jurkat TAg cells, initiated by interaction with the EphA2 receptor, leads to inhibition of activation-induced cell death. To conclude, ephrin-A signaling in Jurkat TAg cells leads to induced phosphorylation of several proteins including Lck, Fyn, and Akt. A consequence of ephrin-A signaling is inhibition of antigen receptor-induced apoptosis.

Key Words: Jurkat • CD3 • cell death • tyrosine kinases