ARHGAP4-SEPT2-SEPT9 complex enables both up- and down-modulation of integrin-mediated focal adhesions, cell migration, and invasion

Abstract

The Rho family of GTPases are inactivated in a cell context-dependent manner by Rho-GTPase-activating proteins (Rho-GAPs), but their signaling mechanisms are poorly understood. Here we demonstrate that ARHGAP4, the Rho-GAPs, forms a complex with SEPT2 and SEPT9 via its Rho-GAP domain and SH3 domain to enable both up- and down-modulation of integrin-mediated focal adhesions (FAs). We show that silencing ARHGAP4 as well as overexpressing its two mutually independent upstream regulators SEPT2 and SEPT9 all induce reorganization of FAs to newly express Integrin Beta 1 and also enhance both cell migration and invasion. Interestingly, even if these cell migration/invasion-associated phenotypic changes are induced upon perturbations to the complex, it does not necessarily cause enhanced clustering of FAs. Instead, its extent depends on whether the microenvironment contains ligands suitable for the upregulated Integrin Beta 1. These results provide novel insights to cell migration, invasion, and microenvironment-dependent phenotypic changes regulated by the newly identified complex.

Human septins organize as octamer-based filaments and mediate actin-membrane anchoring in cells

“…It will be interesting to explore if cortical actin meshworks are also membrane attached through septins ( Vadnjal et al, 2022 ). Septin enrichment adjacent to FAs lets us propose that they also contribute a stabilization function at the connection between FAs and SFs and thus impact FA maturation indirectly ( Calvo et al, 2015 ; Dolat et al, 2014 ; Kang et al, 2021 ) by affecting the accumulation of mechanical tension on SFs.…”

Human septins in cells organize as octamer-based filaments mediating actin-membrane anchoring

“…Our AFM data are in line with such a role, whereby septins stiffen the cell cortex. Although septins are absent from FAs, multiple reports showed that their absence impacts FA maturation (Calvo et al, 2015; Dolat et al, 2014; Kang et al, 2021). Our observation that septin filaments associate as thick fibers adjacent to FAs lets us think that they contribute a stabilization function at the connection between FAs and the core of SFs and thus impact FA maturation indirectly by affecting the accumulation of mechanical tension on SFs.…”

Borg3 controls septin recruitment for primary cilia formation

“…Tuba and intersectin 2 are two promising candidates as GEFs (32, 33). Moreover, GAPs for Rho-GTPases have appeared in ciliary proteomes (38, 39) and might be potential interaction partners for septins (40).…”