EphrinB reverse signaling in cell-cell adhesion: is it just par for the course?
Cell-cell adhesion is a critical process for the formation and maintenance of tissue patterns during development, as well as invasion and metastasis of cancer cells. Although great strides have been made regarding our understanding of the processes that play a role in cell-cell adhesion, the precise mechanisms by which diverse signaling events regulate cell and tissue architecture is poorly understood. In this commentary we will focus on the Eph/ephrin signaling system, and specifically how the ephrinB1 transmembrane ligand for Eph receptor tyrosine kinases sends signals affecting cell-cell junctions. In a recent study using the epithelial cells of early stage Xenopus embryos, we have shown that loss- or gain-of function of ephrinB1 can disrupt cell-cell contacts and tight junctions. This study reveals a mechanism where ephrinB1 competes with active Cdc42 for binding to Par-6, a scaffold protein central to the Par polarity complex (Par-3/Par-6/Cdc42/aPKC) and disrupts the localization of tight junction-associated proteins (ZO-1, Cingulin) at tight junctions. This competition reduces aPKC activity critical to maintaining and/or forming tight junctions. Finally, phosphorylation of ephrinB1 on specific tyrosine residues can block the interaction between ephrinB1 and Par-6 at tight junctions, and restore tight junction formation. Recent evidence indicates that de-regulation of forward signaling through EphB receptors may play a role in metastatic progression in colon cancer. In light of the new data showing an effect of ephrinB reverse signaling on tight junctions, an additional mechanism can be hypothesized where de-regulation of ephrinB1 expression or phosphorylation may also impact metastatic progression.
Lee
Hyun-Shik
HS
Laboratory of Cell and Developmental Signaling, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
Daar
Ira O
IO
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion; D036387:Ephrin-B1 / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D015398:Signal Transduction; D019108:Tight Junctions / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D036387:Ephrin-B1