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Cancer often arises by the constitutive activation of mitogenic pathways by mutations in stem cells. Eph receptors are unusual in that although they regulate the proliferation of stem/progenitor cells in many adult organs, they typically fail to transform cells. Multiple ephrins and Eph receptors are often co-expressed and are thought to be redundant, but we here describe an unexpected dichotomy with two homologous ligands, ephrin-B1 and ephrin-B2, regulating specifically migration or proliferation in the intestinal stem cell niche. We demonstrate that the combined activity of two different coexpressed Eph receptors of the A and B class assembled into common signaling clusters in response to ephrin-B2 is required for mitogenic signaling. The requirement of two different Eph receptors to convey mitogenic signals identifies a new type of cooperation within this receptor family and helps explain why constitutive activation of a single receptor fails to transform cells.We demonstrate that ephrin-B1 and ephrin-B2 have largely non-overlapping functions in the intestinal stem cell niche.Ephrin-B1 regulates cell positioning and ephrin-B2 regulates cell proliferation in the intestinal stem cell niche.EphA4/B2 receptor cooperation in response to ephrin-B2 binding is obligatory to convey mitogenic signals in the intestine.EphA4 facilitates EphB2 phosphorylation in response to ephrin-B2 in SW480 adenocarcinoma cells.Ephrin-B1 and ephrin-B2 induce phosphorylation and degradation of the EphB2 receptor with different kinetics.