CD151, a transmembrane
protein of the
tetraspanin family, is implicated in the regulation of cell-substrate adhesion and cell migration through physical and functional interactions with
integrin receptors. In contrast, little is known about the potential role of CD151 in controlling cell proliferation and survival. We have previously shown that β4
integrin, a major CD151 partner, not only acts as an adhesive receptor for laminins but also as an intracellular signaling platform promoting cell proliferation and invasive growth upon interaction with Met, the
tyrosine kinase receptor for
hepatocyte growth factor (HGF). Here we show that RNAi-mediated silencing of CD151 expression in
cancer cells impairs HGF-driven proliferation, anchorage-independent growth, protection from anoikis, and
tumor progression in xenograft models in vivo. Mechanistically, we found that CD151 is crucially implicated in the formation of signaling complexes between Met and β4
integrin, a known amplifier of HGF-induced
tumor cell growth and survival. CD151 depletion hampered HGF-induced phosphorylation of β4
integrin and the ensuing Grb2-Gab1 association, a signaling pathway leading to MAPK stimulation and cell growth. Accordingly, CD151 knockdown reduced HGF-triggered activation of MAPK but not AKT signaling cascade. These results indicate that CD151 controls Met-dependent neoplastic growth by enhancing receptor signaling through β4
integrin-mediated pathways, independent of cell-substrate adhesion.