We previously demonstrated that CD151 forms a functional complex with c-Met and integrin alpha 3/alpha 6 in human salivary gland cancer cells. In the current study, we investigated the involvement of CD151, c-Met, and integrin alpha 3/alpha 6 in the cellular morphogenesis of human breast cancer cells, Knockdown of CD151, integrin alpha 3, or integrin alpha 6 expression abolished branching morphogenesis. Decreased c-Met expression in these cells led to the formation of rudimentary networks and prevented their conversion. Furthermore, hepatocyte growth factor (HGF) promoted cellular morphogenesis by accelerating network reorganization. Immunoprecipitation revealed a specific association between CD151 and c-Met, The involvement of CD151 and integrin alpha 3/alpha 6 in HGF-depenclent signaling was confirmed by the decreased Akt phosphorylation in cells lacking CD151, integrin alpha 3, or integrin alpha 6. Hence, the regulation of CD151 expression might contribute to changes in HGF/c-Met signaling and thereby modulate the phenotypic characteristics of cancer cells. (C) 2009 Elsevier Inc. All rights reserved.