The C-terminus of ephrin-B1 regulates metalloproteinase secretion and invasion of cancer cells

Abstract

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.

Nm23-H1 regulates contact inhibition of locomotion which is affected by ephrin-B1

“…However, we do not have any evidence at present that ephrin-B1 directly activates the GEF activity of Tiam1, and overexpression of ephrin-B1 did not affect the physical interaction of N-cadherin with b-and a-catenin (data not shown). As one of the mechanisms of ephrin-B1-mediated enhancement of cancer cell invasion, we previously reported that the C-terminus of ephrin-B1 regulates the exocytosis of matrix metalloproteinase (MMP) through the activation of Arf1 GTPase (Tanaka et al, 2007a). We detected elevation of MMP-1 and slight increase in the invasion of collagen by U87MG cells overexpressing ephrin-B1 (supplementary material Fig.…”

“…Although investigation of the functions of Eph receptors and ephrins has focused on the development of the vascular and nervous systems, the roles of Eph-ephrin pathways in epithelial cells and cancers have also attracted interest (Batlle et al, 2005;Holmberg et al, 2006;Castaño et al, 2008;Vaught et al, 2008). We previously observed that signaling through ephrin-B1 is involved in the promotion of carcinomatous peritonitis of gastric cancer and pancreas cancer (Tanaka et al, 2007a;Tanaka et al, 2007b;Tanaka et al, 2010).…”

A functional genetic screen reveals new regulators of β1-integrin activity

“…3F). Because MMP8 is secreted into the medium (Tanaka et al, 2007), we hypothesized that MMP8 could inactivate integrins by binding to the receptor on the 1D). siRNAs inducing downregulation or upregulation of b1-integrin activity in at least four cell lines are indicated with coloured gene IDs in the right column together with the total number of siRNAs affecting 9EG7 or 12G10 binding (z-score ,-1 or .+1) in all of the cell lines studied (numbers in black on the right column).…”

Wnt/Planar cell polarity signaling: A new paradigm for cancer therapy

“…Members of the ephrinB family are often overexpressed in cancer cells and are associated with angiogenesis and metastasis (45). Although several studies provide insight into how ephrinB1-mediated reverse signaling contributes to invasion of gastric and pancreas cancer cells (46,47), recent evidence reveals that intracellular domain of ephrinB1 interacts with Dvl and modulates PCP signaling to control cell adhesion and movement in development (48)(49)(50). This opens up the possibility to explore the potential crosstalk between ephrinB and PCP signaling in the context of tumor cell invasion and metastasis.…”