Mechanisms of Cross-talk Between EphrinB and Alternate Signaling Pathways

Division Of Basic Sciences - Nci

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Abstract

Since, we have gained substantial insight into the mechanisms by which ephrinB signaling is accomplished, we intend to consider these mechanisms in a broader context. For example, how does the interaction between Eph/ephrin and other signaling pathways coordinate morphogenesis? It is important to regard Eph/ephrin signaling as part of a signaling network, rather than an isolated signaling pathway that allows individual cells or subpopulations of cells to receive numerous signals that have to be immediately integrated and translated into coordinated cellular responses. Interactions between Eph/ephrin and other pathways (such as Wnt, and FGF) serve as an apparatus to organize the extracellular inputs received by cells at critical determination points to direct a morphogenetic outcome. This upstream "cross-talk" between pathways eliminates the requirement for a specific signaling cascade for each extracellular cue, and when this signaling system goes awry a disease state (such as birth defects and cancer progression) may be the outcome. One prescient example of how EphB/ephrinB interactions and cross-talk with the Wnt pathway may have direct relevance to cancer are found in studies of colon cancer (Battle et al, Nature 2005; De Lau et al, Front. Biosci. 2007), where EphB receptors compartmentalize the expansion of colorectal cancer cells through a mechanism dependent on E-cadherin-mediated adhesion. This compartmentalization restricts the spreading of EphB-expressing tumor cells into ephrinB1-positive territories in vivo. Thus, colorectal cancer cells must silence EphB expression to prevent repulsive interactions initiated by normal ephrinB1-expressing intestinal cells during tumor progression. Although the bidirectional signaling between ephrinBs and their receptors is quite complex, it is clear that control of expression and the interplay between these proteins may have important effects on malignant transformation. Thus, the cross-talk between the Wnt and Eph/Ephrin systems also operates to limit progression of colorectal cancer after its initiation, and an understanding of the interactions between members of these pathways is a goal of our laboratory. Our laboratory uses an interdisciplinary approach to research by integrating the use of biochemical and developmental techniques to further our studies. We also seek collaborations with other laboratories whose expertise and technologies will complement and strengthen our science. We are continuing to participate in several exciting studies with groups from other academic institutions, and within the NCI (see Collaborations section for list and brief description).