TGFβ-induced changes in membrane curvature influence Ras oncoprotein membrane localization

In the course of cancer progression the tumor cells undergo morphology changes that lead to increased motility and invasiveness promoting formation of metastases. This process called epithelial to mesenchymal transition (EMT) is triggered by transforming growth factor (TGFβ) but for gaining the full invasive potential an interplay between signaling of TGFβ and Ras GTPases is required. Ras proteins possess lipidated domain that mediates Ras association with plasma membrane, which is essential for Ras biological functions. Type and number of the lipid anchors are the main difference among three Ras variants – H-ras, N-ras and K-ras. The lipid anchors determine membrane partitioning of lipidated proteins into membrane areas of specific physico-chemical properties and curvature. In this study, we investigated the effect of TGFβ treatment on subcellular localization of H-ras and K-ras. We show that TGFβ induces increase in positive membrane curvature, which is subsequently sensed by activated H-ras, leading to its elevated plasma membrane localization. This observation suggests an existence of positive feedback loop in which increased level of membrane curvature of plasma membrane during TGFβ induced EMT would attract more Ras molecules to plasma membrane resulting in increased Ras activity and subsequent further promotion of EMT and acquisition of invasive potential.