MORPHOGENETIC EFFECTS OF NEUREGULIN (NEU DIFFERENTIATION FACTOR) IN CULTURED EPITHELIAL-CELLS

Neuregulin, or neu differentiation factor, induces cell proliferation or differentiation through interaction with members of the ErbB family of receptor tyrosine kinases. We report that neuregulin can also indu ce profound morphogenic responses in cultured epithelial cells of diff erent origins. These effects include scattering of small epithelial is lands and rearrangement of larger cell islands into ordered ring-shape d arrays with internal lumens. The ring-forming cells are interconnect ed by cadherin- and beta-catenin-containing adherens junctions. In con fluent cultures, neuregulin treatment induces formation of circular lu menlike gaps in the monolayer. Both cell scattering and ring formation are accompanied by a marked increase in cell motility that is indepen dent of hepatocyte growth factor/scatter factor and its receptor (c-Me t). Affinity-labeling experiments implied that a combination of ErbB-2 with ErbB-3 mediates the morphogenic signal of neuregulin in gastric cells. Indeed, a similar morphogenic effect could be reconstituted in nonresponsive cells by coexpression of ErbB-2 and -3. We conclude that a heterodimer between the kinase-defective neuregulin receptor, ErbB- 3, and the coreceptor, ErbB-2, mediates the morphogenetic action of ne uregulin.