Lipid raft protein flotillin‐1 is important for the interaction between SOS1 and H‐Ras/K‐Ras, leading to Ras activation

Ras mutations have been frequently observed in human cancer. Although there is a high degree of similarity between Ras isomers, they display preferential coupling in specific cancer types. The binding of Ras to the plasma membrane is essential for its activation and biological functions. The present study elucidated Ras isoform‐specific interactions with the membrane and their role in Ras‐mediated biological activities. We investigated the role of a lipid raft protein flotillin‐1 (Flot‐1) in the activations of Ras. We found that Flot‐1 was co‐localized with H‐Ras, but not with N‐Ras, in lipid rafts of MDA‐MB‐231 human breast cells. The amino‐terminal hydrophobic domain (1‐38) of Flot‐1 interacted with the hypervariable region of H‐Ras. The epidermal growth factor‐stimulated activation of H‐Ras required Flot‐1 which was not necessary for that of N‐Ras in breast cancer cells. Flot‐1 interacted with son of sevenless (SOS)‐1, which promotes the conversion of Ras‐bound GDP to GTP. Notably, Flot‐1 was crucial for the interaction between SOS1 and H‐Ras/K‐Ras in breast and pancreatic cancer cells. Stable knockdown of Flot‐1 reduced the in vivo metastasis in a mouse xenograft model with human breast carcinoma cells. A tissue microarray composed of 61 human pancreatic cancer samples showed higher levels of Flot‐1 expression in pancreatic tumor tissues compared to normal tissues, and a correlation between K‐Ras and Flot‐1. Taken together, our findings suggest that Flot‐1 may serve as a membrane platform for the interaction of SOS1 with H‐Ras/K‐Ras in human cancer cells, presenting Flot‐1 as a potential target for Ras‐driven cancers. What's new? The binding of Ras mutant isoforms, which are frequently observed in human cancers, to the plasma membrane is essential for their biological functions. The molecular mechanisms underlying Ras isoform‐specific activation however remain unclear. Our study showed that the membrane lipid raft protein Flotillin‐1 was crucial for the interaction between SOS1 and H‐Ras/K‐Ras and subsequent Ras activation in human breast and pancreatic cancer cells. Flotillin‐1 knockdown delayed breast cancer metastasis in a xenograft mouse model. The findings suggest that Flotillin‐1 may serve as a membrane platform for SOS1 and H‐Ras/K‐Ras interactions and identify Flotillin‐1 as a potential target in Ras‐driven cancers.