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  • Whilst it has long been appreciated that Rho family GTPases

    2022-06-23

    Whilst it has long been appreciated that Rho-family GTPases are able to signal directly to focal adhesions, it is also becoming increasingly clear that they can achieve this indirectly, through their influence on the extracellular matrix to which the integrins bind. Cdc42 and RhoA have long been known to promote the trafficking of metalloproteinases to the tips of invadopodia to promote cancer cell SQ 29,548 by driving an interaction between IQGAP with the exocyst complex [52]. More recently a study has established a clear link between Cdc42 and fibronectin deposition allowing for the formation of focal adhesions within lamellipodia and permitting migration over the resulting matrix in a Rac1-dependent manner []. Given that filopodia drive cancer cell invasion into fibronectin containing matrix [23,54], it will be fascinating to discover if filopodia can also drive fibronectin deposition in vivo. Whilst cell–matrix interactions are relatively well understood in 2D, it is vital that these studies are translated to 3D in vivo systems SQ 29,548 given the stark biochemical and mechanical differences between such systems. Understanding how Rho-family GTPases coordinate cell–matrix interactions in vivo is particularly challenging given the technical difficulties that are associated with studying cell–matrix receptors, such as integrins, in 3D. However, studying how Rho-GTPases coordinate cell matrix interactions in vivo is essential to understanding cell migration, in contexts such as wound healing and cancer.
    Conclusion
    Conflict of interest statement
    References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
    Acknowledgements The Wellcome Trust Centre for Cell-Matrix Research is supported by grant 203128/Z/16/Z. Cancer Research UK PhD studentship grant C147/A19404. BJW is supported by a Wellcome Trust PhD studentship grant 109330/Z/15/A.
    Main Text With 11 proteins in yeast and over 60 in humans, Rab GTPases control membrane identity, maturation, trafficking, autophagy, and other processes throughout the eukaryotic endomembrane system (Hutagalung and Novick, 2011). These conserved molecular switches depend on selective interactions with guanine nucleotide exchange factors (GEFs) and GTPases activating proteins (GAPs) that control activation and deactivation, respectively, as well as effectors that mediate functional outputs by recognizing the GTP-bound active but not GDP-bound inactive conformation. Rab GTPases require prenylation (typically dual geranyl geranylation) of C-terminal cysteines for membrane association and have complex/overlapping spatiotemporal distributions essential for functional specificity and coordination. In addition to the GTPase domain, Rab proteins have distinctive N- and C-terminal extensions referred to as hypervariable domains (HVDs). The HVDs diverge with respect to length and sequence, apart from the prenylated cysteines and cryptic sequence features implicated in interactions with Rab Escort Protein (REP) and Rab GDP-dissociation inhibitor (RabGDI) (Goody et al., 2005). REP, RabGDI, and in some cases a GDI displacement factor (Sivars et al., 2003) are required for prenylation and delivery of prenylated Rabs to membranes. Since RabGDI extracts GDP- but not GTP-bound Rabs from membranes, the sites where Rabs are activated depend mainly on the localization and substrate selectively of the GEFs (Cabrera and Ungermann, 2013). The spatiotemporal distributions of active Rabs are subsequently influenced by the localization and specificity of GAPs and effectors, which compete for the GTP-bound conformation, and by membrane maturation/trafficking processes. A role for the HVDs in localization and functional specificity was originally suggested by experiments with chimeric Rab proteins. Localization can be converted, impaired, or unaffected by replacement of the C-terminal HVD with that of another Rab or a polyethylene glycol linker (Li et al., 2014). Converting functional specificity typically requires additional substitutions in the GTPase domain, and specificity determinants for GEFs, GAPs, effectors, and REP/RabGDI have been identified in the switch regions, proximal structural elements, and HVDs. The molecular and structural bases are complex, idiosyncratic, and incompletely understood.