Tissue transglutaminase clusters soluble A-type ephrins into functionally active high molecular weight oligomers.
The Eph receptors and their ligands, the ephrins, are thought to act at points of close cell-cell contact to elicit bi-directional signaling in receptor and ligand expressing cells. However, when cultured in vitro, some A-type ephrins are released from the cell surface and it is unclear if these soluble ephrins participate in Eph receptor activation. We show that soluble ephrin A5 is subject to oligomerization. Ephrins A1 and A5 are substrates for a cross-linking enzyme, tissue transglutaminase, which mediates the formation of oligomeric ephrin. Transglutaminase-cross-linked ephrin binds to A-type Eph receptors, stimulates Eph kinase activity, and promotes invasion and migration of HeLa cells. Transglutaminase-mediated oligomerization of soluble ephrin potentially represents a novel mechanism of forward signaling through Eph receptors and may extend the influence of A-type ephrins beyond cell contact mediated signaling.
Alford
Spencer C
SC
Centre for Biomedical Research, University of Victoria, PO Box 3020 Station CSC Victoria, BC, Canada V8W 3N5.
Bazowski
Jessa
J
Lorimer
Heather
H
Elowe
Sabine
S
Howard
Perry L
PL
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D036342:Ephrins / Q000737:chemistry* / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008970:Molecular Weight; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D020836:Protein Structure, Quaternary; D034622:RNA Interference; D036081:Receptors, Eph Family / Q000378:metabolism; D012995:Solubility / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D014162:Transfection; D011503:Transglutaminases / Q000378:metabolism*
D000906:Antibodies; D003432:Cross-Linking Reagents; D036342:Ephrins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D036081:Receptors, Eph Family; D019204:GTP-Binding Proteins