Integrin-mechanosignaling role in small GTPases activation and cancer.

FASSLER R; CURINO AC; FACCHINETTI MM; COLÓ G

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias. LXII Reunión Anual de la Sociedad Argentina de Investigaciones Clínicas (SAIC); 2017

Sociedad Argentina de Investigación Clínica

The ability of cells to adhere and simultaneously probe their mechanical environment is central to many developmental, homeostatic but also pathological processes. Yet, the molecular mechanisms that govern mechanotransduction during cell adhesion and invasion are complex and remain incompletely understood. We determined the importance of studying integrins in genetically modified cell models that only express the family of fibronectin-binding integrins, in non-invasive and invasive cancer cell lines. Using biochemical assays in combination with mass spectroscopy, traction force microscopy and micropatterns, we observed that α5β1-integrins (pKO-β1) promote the formation of small nascent adhesions (NAs) with high turnover, low RhoA activation and high force, while αVβ3 (pKO-αV) promotes adhesion maturation leading to large focal adhesions connected to contractile stress fibers (SFs) resulting in high RhoA and low force, while cells expressing both integrins contain small and large adhesion structures and intermediated GTPases activites. Therefore, it is essential to identify and characterize signalling molecules and pathways between specific integrins and small Rho GTPases and how they control mechanotransduction during cell migration and tumor cell invasion. Rho GTPases are activated by Guanine Nucleotide Exchange Factors (GEFs) and inactivated by Rho GTPase-activating proteins (GAPs). We observed that integrins regulate Rho GTPases through regulating GEFs and GAPs. Consequently, specific integrin-class expression and Gactin polymerization induce MRTF-A/SRF activation and the ubiquitin-like modifier interferon-stimulated gene 15 (ISG15) expression that promotes cell migration and invasion. The future findings have important implications for our understanding of cancer progression and will help identifying new targets for future therapies.