title: In human leukemia cells ephrin-B-induced invasive activity is supported by Lck and is associated with reassembling of lipid raft signaling complexes.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Regina, Regina, SK, Canada.
authors.forename: Guangping
authors.initials: G
authors.lastname: Jiang
authors.forename: Tanya
authors.initials: T
authors.lastname: Freywald
authors.forename: Jarret
authors.initials: J
authors.lastname: Webster
authors.forename: Daniel
authors.initials: D
authors.lastname: Kozan
authors.forename: Ron
authors.initials: R
authors.lastname: Geyer
authors.forename: John
authors.initials: J
authors.lastname: DeCoteau
authors.forename: Aru
authors.initials: A
authors.lastname: Narendran
authors.forename: Andrew
authors.initials: A
authors.lastname: Freywald
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002448:Cell Adhesion; D002648:Child; D036387:Ephrin-B1 / Q000737:chemistry / Q000378:metabolism*; D036389:Ephrin-B3 / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology* / Q000473:pathology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D021962:Membrane Microdomains / Q000201:enzymology*; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D036387:Ephrin-B1; D036389:Ephrin-B3; D005353:Fibronectins; D009687:Nuclear Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D020830:rac1 GTP-Binding Protein