The C-terminus of ephrin-B1 regulates metalloproteinase secretion and invasion of cancer cells.
Interaction of the Eph family of receptor protein tyrosine kinases and their ligands, ephrin family members, induces bi-directional signaling via cell-cell contacts. High expression of B-type ephrin is associated with high invasion potential of tumors, however, the mechanism by which ephrin-B promotes cancer cell invasion is poorly understood. We show that interaction of ephrin-B1 with the Eph receptor B2 (EphB2) significantly enhances processing of the extracellular domain of ephrin-B1, which is regulated by the C-terminus. Matrix metalloproteinase-8 (MMP-8) is the key protease that cleaves ephrin-B1, and the C-terminus of ephrin-B1 regulates activation of the extracellular release of MMP-8 without requirement of de novo protein synthesis. One possible mechanism by which ephrin-B1 regulates the exocytosis of MMP-8 is the activation of Arf1 GTPase, a critical regulator of membrane trafficking. In support of this hypothesis, activation of ephrin-B1 increased GTP-bound Arf1, and the secretion of MMP-8 was reduced by expression of a dominant-negative mutant of Arf1. Expression of ephrin-B1 promoted the invasion of cancer cells in vivo, which required the C-terminus of ephrin-B1. Our results suggest a novel function of the C-terminus of ephrin-B1 in activating MMP-8 secretion, which promotes the invasion of cancer cells.
Tanaka
Masamitsu
M
Department of Growth Factor Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Tokyo 104-0045, Japan.
Sasaki
Kazuki
K
Kamata
Reiko
R
Sakai
Ryuichi
R
D020823:ADP-Ribosylation Factor 1 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D036387:Ephrin-B1 / Q000096:biosynthesis* / Q000235:genetics; D005089:Exocytosis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000235:genetics; D020298:U937 Cells
C484288:EFNB1 protein, human; D036387:Ephrin-B1; D009363:Neoplasm Proteins; D006160:Guanosine Triphosphate; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8; D020823:ADP-Ribosylation Factor 1