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.
Highlights
The members of the Eph receptor family can be classified into two groups based on their sequence similarity and their preferential binding to ligands tethered to the cell surface either by a glycosylphosphatidyl inositol anchor or a transmembrane domain (Murai and Pasquale, 2003; Blits-Huizinga et al, 2004; Poliakov et al, 2004)
The Ephrin-B1 ectodomain is secreted into the culture medium of pancreatic cancer cell lines During screening of peptides secreted by the pancreatic cancer cell line SUIT-4, we identified,using MALDI-MS/MS analysis, three different peptides derived from ephrin-B1 sharing a common N-terminus
Cleavage of ephrin-B1 ectodomain is enhanced by interaction with its receptor Eph receptor B2 (EphB2), which is regulated by the C-terminus of ephrin-B1 we examined whether the interaction of ephrin-B1 with its receptor EphB2 modifies the cleavage of ephrin-B1
Summary
The members of the Eph receptor family can be classified into two groups based on their sequence similarity and their preferential binding to ligands tethered to the cell surface either by a glycosylphosphatidyl inositol anchor (ephrin-A) or a transmembrane domain (ephrin-B) (Murai and Pasquale, 2003; Blits-Huizinga et al, 2004; Poliakov et al, 2004). Ephrin-B has an intracellular domain, which includes sites for tyrosine phosphorylation via Src family kinases and a docking site for proteins with a PDZ domain (Lin et al, 1999; Cowan and Henkemeyer, 2001; Bong et al, 2004). These sites give ephrinB ligands at least two ways of being involved in intracellular signaling. Overexpression of B-type ephrin in cancer cells is reported to correlate with high invasion and high vascularity of tumors (Meyer et al, 2005; Castellvi et al, 2006; Nakada et al, 2006), and elevated expression of ephrin-B1 is observed in poorly differentiated invasive tumor cells and other tumors with poor clinical prognosis (Kataoka et al, 2002; Varelias et al, 2002)
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