EphrinB1 controls cell–cell junctions through the Par polarity complex

Abstract

A body of evidence is emerging that shows a requirement for ephrin ligands in the proper migration of cells, and the formation of cell and tissue boundaries. These processes are dependent upon the cell-cell adhesion system that plays a critical role in normal morphogenetic processes during development, as well as in invasion and metastasis1–9. Although ephrinB ligands are bi-directional signaling molecules, the precise mechanism by which ephrinB1 signals through its intracellular domain to regulate cell-cell adhesion in epithelial cells has remained elusive. Here, we present evidence that ephrinB1 associates with the Par polarity complex protein, Par-6, a scaffold protein required for establishing tight junctions, and can compete with the small GTPase Cdc42 for an association with Par-6. This competition results in inactivation of the Par complex, resulting in the loss of tight junctions. Moreover, the interaction between ephrinB1 and Par-6 is disrupted upon tyrosine phosphorylation of the intracellular domain of ephrinB1. Thus, we have identified a mechanism by which ephrinB1 signaling regulates cell-cell junctions in epithelial cells, and this may impact how we devise therapeutic interventions regarding these molecules in metastatic disease.

Deregulated ephrin-B2 signaling in mammary epithelial cells alters the stem cell compartment and interferes with the epithelial differentiation pathway

“…7B). Combining Sca-1 expression with CD49b expression, the integrin-α2 thought to represent a marker of luminal precursor cells (39), confirmed the increase of Sca-1 positive cells in the stem cell-enriched fraction (Fig. 7C).…”

“…The confocal analyses of these two proteins revealed severe perturbations in their expression and sub-cellular co-localization which might have led to the observed reduction in apoptotic cell death and lumen formation in the ∆ephrinB2 outgrowths. It has been shown that ephrin-B1 reverse signaling not only is controlled by and regulates adherens junctions but is also involved in the establishment of functional tight junctions (39). Furthermore, screening for PDZ-interacting proteins of ephrins-B1-3 revealed a Par-3 homolog to be a major ephrin-interacting protein (53).…”

A novel genetic mechanism regulates dorsolateral hinge-point formation during zebrafish cranial neurulation

“…Eph/ephrin signaling has been shown to regulate adhesion and junctions in epithelial cells (Lee, H. S. et al, 2008;Pasquale, 2005). EphB1 transcription is activated by Zic2 during retinal ganglion cell guidance in mouse (Lee, R. et al, 2008).…”

Gbx2 and Fgf8 are sequentially required for formation of the midbrain-hindbrain compartment boundary

“…Furthermore, activation of FGF signaling has a cell-autonomous role in controlling cell sorting in the mes. Finally, previous studies have shown that Fgfr1 is required for the expression of Cdh22, which encodes the cell adhesion molecule PB-cadherin, in the posterior mes (Trokovic et al, 2003), and that FGF signaling modulates ephrin and catenins in regulating cell-cell interactions (Lee et al, 2009;Lee et al, 2008;Lilien et al, 2002). As Fgf8-expressing cells form a tight transverse band in the isthmus, the mes cells immediately anterior to the MHB probably receive high levels of Fgf8 and thus display distinct cell adhesive characteristics.…”