Ephrin-A1 binding to CD4+ T lymphocytes stimulates migration and induces tyrosine phosphorylation of PYK2.
Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands are important mediators of cell-cell communication regulating cell attachment, shape, and mobility. Here we demonstrate that CD4+ T lymphocytes express the EphA1 and EphA4 receptors and that these cells bind the ligand ephrin-A1. Further we show ephrin-A1 expression in vivo on high endothelial venule (HEV) endothelial cells. Ephrin-A1 binding to CD4+ T cells stimulates both stromal cell-derived factor 1alpha (SDF-1alpha)- and macrophage inflammatory protein 3beta (MIP3beta)-mediated chemotaxis. In line with the increased chemotactic response, increased actin polymerization is observed in particular with the combination of ephrin-A1 and SDF-1alpha. Signaling through EphA receptors induces intracellular tyrosine phosphorylation. In particular, proline-rich tyrosine kinase 2 (PYK2) is phosphorylated on tyrosine residues 402 and 580. Ephrin-A1-induced chemotaxis and intracellular tyrosine phosphorylation, including EphA1 and Pyk2, was inhibited by Tyrphostin-A9. In conclusion, ligand engagement of EphA receptors on CD4+ T cells stimulates chemotaxis, induces intracellular tyrosine phosphorylation, and affects actin polymerization. This, together with our finding that ephrin-A1 is expressed by HEV endothelial cells, suggests a role for Eph receptors in transendothelial migration.
Aasheim
Hans-Christian
HC
Department of Immunology and Pathology, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway. h.c.asheim@labmed.uio.no
Delabie
Jan
J
Finne
Eivind Farmen
EF
D000199:Actins / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement / Q000276:immunology*; D036382:Ephrin-A1 / Q000378:metabolism* / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008221:Lymphoid Tissue / Q000378:metabolism; D010766:Phosphorylation; D011108:Polymers / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D036082:Receptor, EphA1 / Q000235:genetics / Q000378:metabolism; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D014699:Venules / Q000166:cytology / Q000378:metabolism
D000199:Actins; D036382:Ephrin-A1; D007211:Indoles; D011108:Polymers; C416927:SU 6656; D013449:Sulfonamides; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D036082:Receptor, EphA1; D036122:Receptor, EphA4; D051418:Focal Adhesion Kinase 2