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Comprehensive analysis on the whole Rho‐GAP family reveals that ARHGAP4 suppresses EMT in epithelial cells under negative regulation by Septin9

Epithelial to mesenchymal transition (EMT) is a fundamental biological process that occurs during development and tumorigenesis. The Rho family of GTPases (Rho‐family) is a well‐characterized regulator of actin cytoskeleton that gives rise to EMT‐associated cell activities. Meanwhile, there are in total at least 66 different Rho‐GTPase‐activating proteins (Rho‐GAPs), which, as an upstream regulator, inactivate specific members of the Rho‐family in a cell context‐dependent manner. However, molecular roles of individual Rho‐GAPs are poorly understood, particularly regarding their involvements in EMT. Here, based on comprehensive screening on the whole Rho‐GAP family, we identified specific Rho‐GAPs that are responsible for the maintenance of epithelial cell phenotypes, suppressing EMT in human mammary epithelial cells. Specifically, we revealed that at least two Rho‐GAPs, that is, ARHGAP4 and SH3BP1, critically regulate the cell morphology. Among them, we focused on ARHGAP4 and demonstrated with multidisciplinary approaches that this specific Rho‐GAP regulates epithelial/mesenchymal‐selective marker expression, cell proliferation, migration, 3D morphogenesis, and focal adhesion/stress fiber‐driven physical force generation in a manner reminiscent of the EMT process. Furthermore, we identified Septin9 with proteomic analyses as a negative regulator of ARHGAP4, which promotes the occurrence of EMT by activation of the FAK/Src signaling pathway. These findings shed light on the novel Rho‐GAP‐associated pathway in the EMT process under development and tumorigenesis.