Integrin-mechanosignaling role in small GTPases activation and cancer

COLÓ, G.P.; BARRERA LAMAS, N.; MASCARÓ, M.; FÄSSLER, R; FERNÁNDEZ CHAVÉZ, L.; GANDINI, N.A.; PICHEL, P.; FACCHINETTI, M.M.; SCHWEITZER, K.; ALONSO, E.G.; RECIO, S.; CURINO, A.C.

Mar del Plata

Congreso; LXIV Reunión Anual de SAIC; 2019

Over the past decade there has been a big effort towards identifying key moleculesand signaling pathways relevant to cellular mechanobiology and pathological process.External force is sensed by cells using simple receptors and a complex transductionmachinery. The anchors of this complex machine are the transmembrane receptorscalled integrins which connect and transform out-side to in-side signaling through thefocal adhesion formation, GTPases activation and myosin phosphorylation by ROCKkinase, transforming the chemical energy (ATP) into mechanical (force)1,2. Integrinsconnect cells to a wide range of extracellular matrix (ECM) proteins includingfibronectin (FN), vitronectin, collagens and laminins as well as other cell surfacereceptors like VCAM and ICAM3. Most cell types express a number of integrin receptorsubtypes simultaneously which can synergize, for example to amplify myosindependentsignal transduction cascades4. In addition, actin cytoskeleton is modulatedand controlled by small Rho-GTPases as well as non-muscle myosin II activity. Thus,the actomyosin network does not only generate mechanical force but also acts as amajor mechanosensitive element in the outer layer of focal adhesion (FA)5.On the other hand, little is known regarding the environmental signals that activate themigratory phenotype of tumor cells. Hence, it is essential to identify and characterizesignalling molecules and pathways between specific integrins and small Rho GTPasesand how they control mechanotransduction during cell migration and tumor cellinvasion. Rho GTPases are activated by Guanine Nucleotide Exchange Factors(GEFs) and inactivated by Rho GTPase-activating proteins (GAPs)6.In order to study if FN-binding integrins regulate Rho GTPases activity throughregulating GEFs and GAPs, a proteomic analysis was performed and amongst the interesting hits was the RhoA activator, Guanine Nucleotide Exchange Factor H1 (alsoknown as GEF-H1 in human and Lfc in mouse, encoded by ARHGEF2 gene), togetherwith other less abundant GEFs and GAPs.Tumor progression requires significant remodelling of the tumor environment includingchanges in tissue stiffness and altered functions of various cell types, suggesting thatmolecules involved in ECM sensing and force generation could be a good therapeutictargets for cancer treatment7,8.In addition, recent studies have also shown that an increase in GEF-H1 expressioncorrelates with an increased in tumor progression and metastasis9,10. However, themechanisms that explain how RhoGEF expression is increased in cancer and how itpromotes metastasis remain unknown.Here, we show high GEF-H1 protein expression in thyroid and breast tumor biopsiescompared with normal tissue. Furthermore, GEF-H1 depletion in an invasive breastcancer cell line led to a decrease in proliferation, migration and invasion rates. Theseresults strongly suggest that GEF-H1 is involved in tumor progression.