Rac activation and inactivation control plasticity of tumour cell movement

Tumour Invasion: A New Twist on Rac-Driven Mesenchymal Migration

“…An elongated ('mesenchymal-like') mode is characterized by cell polarization, a requirement for extracellular proteolysis [4], and low actomyosin contractility [5], and is driven by the formation of membrane protrusions that result from a localized activation of the Rac GTPase [6]. Rounded 'amoeboid' modes of cell migration are driven by high levels of actomyosin contractility regulated by Rho-ROCK signalling [5,7] or the Cdc42 GTPase [8]. In rounded moving cells, high hydrostatic forces drive cell movement resulting in membrane blebbing [9].…”

“…Elongated mesenchymal movement can be driven by activation of Rac1 through the GEF DOCK3 complexed with the adaptor protein NEDD9 [5]. Rac1 promotes elongation through WAVE2-mediated actin polymerization [5,10,11].…”

“…Elongated mesenchymal movement can be driven by activation of Rac1 through the GEF DOCK3 complexed with the adaptor protein NEDD9 [5]. Rac1 promotes elongation through WAVE2-mediated actin polymerization [5,10,11]. Furthermore, Rac1 signalling suppresses rounded movement [5,11,12] through decreasing actomyosin contractility [5,12].…”

“…Rac1 promotes elongation through WAVE2-mediated actin polymerization [5,10,11]. Furthermore, Rac1 signalling suppresses rounded movement [5,11,12] through decreasing actomyosin contractility [5,12]. In an effort to identify new functions of Twist1, Yang et al [3] screened for possible new targets with a particular focus on miRNAs.…”

“…The authors confirmed that loss of let-7i induced a morphological switch into a mesenchymal program of invasion [3], with long-lived protrusions that are typical of a Rac-driven phenotype. They went on to find that let-7i downregulated NEDD9 and DOCK3 [3], both of which are activators of Rac and drive mesenchymal movement in several systems [3,5,10,12]. Furthermore, Twist1 overexpression induced Rac1 activation in HNSCCs, as a result of increased expression of both NEDD9 and DOCK3 [3] HNSCC tends to remain localized at the primary site and regional lymph nodes.…”