Eph receptors and their ephrin ligands can limit cell migration through repulsion, a function that underpins their role in axonal guidance. More recently, Eph–ephrins have been found to induce cell proliferation in stem and progenitor cells. To understand how these two different pathways are mediated, the authors inhibited EphB receptor clustering (which leads to activation) in the mouse intestine through the injection of an ephrin-B2–Fc protein. Analysis of gene expression levels in the colonic cells indicated that the expression of genes involved in cell migration was altered earlier than those involved in proliferation.
To follow up, the authors used various EPHB2-mutant receptors and expressed these in the intestines of
EphB3
-null mice. They compared the outcomes with those of
EphB2
−/−
; EphB3−/− mice, which show reduced proliferation and disrupted cell positioning in intestinal crypts owing to migration defects. They found that the expression of kinase-dead EPHB2 reduced proliferation, but did not disrupt cell positioning. Further investigations showed that EPHB2 regulates the activity of cyclin D1 through a pathway involving the kinase ABL1. Indeed, cyclin D1-null mice had reduced proliferation of cells in the colon and were unaffected by the suppression of EphB2 signalling using ephrin-B2–Fc or ABL1 inhibition by imatinib, both of which limit proliferation in the intestines of wild-type mice.
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