RAC-driven cell migration – differential signalling through different GEFs

Even though activation of RAC has been shown to have only positive roles in tumour initiation and growth, it can lead to opposing migratory phenotypes – cell-cell adhesion versus motility – raising the possibility that targeting RAC in a clinical setting could exacerbate tumour progression. This calls for the identification of factors that both influence the selection of RAC-driven cellular processes as well as mediate RAC’s effects. In a recent study (Marei et al. Nature Communications 2016) we demonstrated that two RAC GEFs TIAM1 and P-REX1 promote RAC-driven cell‒cell adhesion and RAC-driven cell migration and invasion respectively, through regulating the RAC interactome. While TIAM1 promotes the association of RAC with proteins known to be important for the formation and maintenance of cell-cell adhesions and consequently inhibits migration, we demonstrated that P-REX1 stimulates migration through enhancing the interaction between RAC and the actin-remodelling protein Flightless-1 homolog (FLII), to modulate cell contraction in a RHOA-ROCK independent manner. Thus, in this study, we provided direct evidence that RAC GEFs are critical determinants of selectivity in signalling events downstream of RAC (see also Marei et al. Small GTPases 2016).

We have additionally shown that the RAC GEF TIAM2/STEF is also required for optimal cell migration via regulating microtubule targeting of focal adhesions, adhesions required for attachment of the cells to their substrate (Rooney et al. EMBO Reports 2010). Moreover we have shown that RAC is post-translationally modified during HGF-induced migration by both SUMOylation and ubiquitylation. SUMOylation leads to the stabilisation of the active form of RAC, and is required for optimal cell migration (Castillo-Lluva et al. Nat Cell Biol. 2010). Ubiquitylation leads to degradation of active RAC and cells lacking HACE1, the ubiquitin ligase responsible for ubiquitylating RAC1, have enhanced cell migration compared to control cells (Castillo-Lluva et al. Oncogene 2013).


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