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Signaling and Regulation

In Human Leukemia Cells Ephrin-B–Induced Invasive Activity Is Supported by Lck and Is Associated with Reassembling of Lipid Raft Signaling Complexes

¹ Department of Chemistry and Biochemistry, University of Regina, Regina, Saskatchewan, Canada; ² Genomic Medicine and Pathobiology Research Group and Departments of Pathology, Medicine, and Biochemistry, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; and ³ Tom Baker Cancer Centre, Calgary, Alberta, Canada

Requests for reprints: Andrew Freywald, Department of Chemistry and Biochemistry, University of Regina, 3737 Wascana Parkway, Regina, SK, Canada S4S 0A2. Phone: 306-585-4192. E-mail: andrew.freywald{at}uregina.ca

Proteins of the ephrin-B group operate in nonlymphoid cells through the control of their migration and attachment, and are crucial for the development of the vascular, lymphatic, and nervous systems. Ephrin-B activity is deregulated in various nonlymphoid malignancies; however, their precise role in cancer has only started to be addressed. We show here that ephrin-B1, a member of the ephrin-B group, is expressed in pediatric T-cell leukemias, including leukemia cell line Jurkat. Treatment of Jurkat cells with ephrin-B–stimulating EphB3 enhances ephrin-B1 phosphorylation and induces its relocalization into lipid rafts. These events are mediated by the T lineage–specific kinase, Lck, as ephrin-B1 phosphorylation and lipid raft association are blocked in the Lck-deficient clone of Jurkat, JCAM1.6. Ephrin-B1 also induces colocalization of the CrkL and Rac1 cytoskeleton regulators and initiates in leukemic cells a strong repulsive response. The absence of Lck blocks ephrin-B1–induced signaling and repulsion, confirming the essential role for Lck in ephrin-B1–mediated responses. This shows a new role for ephrin-B1 in the regulation of leukemic cells through the Lck-dependent Rac1 colocalization with its signaling partner, CrkL, in lipid rafts. In agreement with its repulsive action, ephrin-B1 seems to support metastatic properties of leukemic cells, as suppression of ephrin-B1 signaling inhibits their invasiveness. Because ephrin-B1–activating EphB proteins are ubiquitously expressed, our findings suggest that ephrin-B1 is likely to play an important role in the regulation of malignant T lymphocytes through the control of lipid-raft–associated signaling, adhesion, and invasive activity, and therefore may represent a novel target for cancer treatment. (Mol Cancer Res 2008;6(2):291–305)