ErbB2 resides in lipid rafts (regions of receptor regulation) in vestibular schwannoma (VS) cells.ErbB2 is a growth factor receptor critical for Schwann cell (SC) proliferation and development. ErbB2 localization and activity may be regulated by merlin, an adaptor protein deficient in VS. Lipid rafts are microdomains in the plasma membrane that amplify and regulate receptor signaling. Persistence of erbB2 in lipid rafts in VS due to merlin deficiency may explain increased VS cell growth.Protein extracts from VS or rat sciatic nerve (proximal or distal to a crush injury) were isolated into lipid raft and nonraft fractions and immunoblotted for erbB2, phosphorylated erbB2, and merlin (for sciatic nerve). Cultured VS cells were probed with anti-erbB2 antibody and a lipid raft marker, cholera toxin B (CTB).ErbB2 moves to lipid rafts in proliferating SCs and is persistently localized to lipid rafts in VS cells. ErbB2 is phosphorylated (activated) in lipid rafts. ErbB2 colocalized with CTB in cultured VS cells, confirming raft targeting. Merlin also persistently localized to lipid rafts in SCs, and its relative phosphorylation increased in proliferating cells.Lipid raft localization of erbB2 in proliferating SCs and in VS cells supports a critical role for lipid rafts in amplifying/regulating erbB2 signaling. Merlin resides in lipid rafts in SCs, and its phosphorylation increases in proliferating SCs, suggesting it regulates cell proliferation within lipid rafts. The absence of merlin in VS may therefore lead to persistent erbB2 localization to lipid rafts and increased cell proliferation.