Regulation of RhoGTPases in motility: A fine balancing act

Cell migration is vitally important under physiological conditions such as in development, immune response, wound healing and in maintenance of the tissue homeostasis. These processes are aberrantly dysregulated in pathologic conditions and thus, altered regulation of cell migration results in many human diseases including developmental defects, inflammatory diseases and malignant cancers. One of the critical components of cell motility and migration is the cellular actin machinery that drives the cell locomotion. In recent years, regulatory mechanisms are being elucidated that involve Rho family of small GTP-binding proteins (GTPase), regulated by the balance of their upstream regulators Guanine-nucleotide Exchange Factors (GEF), GTPase Activating Proteins (GAPs) and the Guanine-nucleotide Dissociation Inhibitor (GDI). The specificity of signal regulation and transduction is critically dependent on the integration of correct spatial and temporal cues that dictate the RhoGTPase activation status within subcellular scales and time resolution in the order of seconds. In this special section, we focus on the current state of the field in RhoGTPase signaling, and approach it from the stand point of RhoGTPase isoform specificity and the upstream GEF-specificity that, in part, drive the ensemble of actin-based motility machinery, ultimately orchestrating the coordinated cellular migratory behaviors, both under normal and pathologic conditions.

RhoGTPases classically associated with cellular actin cytoskeleton regulation and motility are RhoA, Rac1 and Cdc42. However, close isoforms that share up to 90+% primary amino acid sequence but arise from separate gene products exist, and they appear to regulate very different functions from the classical RhoGTPases. The expression profiles of these isoforms of RhoGTPases in different cell types appear to suggest differential roles in many disease-specific situations that are not yet fully elucidated. Here, Donnelly et al.¹ reviews these aspects of RhoGTPase isoforms and their often very diverse signaling pathways they may regulate, which are important in both normal and pathologic conditions.

RhoGTPases require precise activation timings and spatial localizations in order to direct many cellular functions they regulate. It is becoming clearer that this is exquisitely controlled by regulation of the upstream regulators of RhoGTPases, including the GEFs, GAPs and GDI. Here, Goicoechea et al.² comprehensively reviews the mechanisms and functions of GEFs as they pertain to specific cellular motility components, polarization functions and adhesions and migrations.

Together with the previously published series of reviews on the kinase-mediated regulation of GEFs (Patel and Karginov³), and the functional roles of these orchestrated effects of GEF-targets and RhoGTPase isoform-specific effects during leukocyte-endothelium transmigration (Heemskerk et al.⁴), we present an overview of the fine balancing act that is the regulation of RhoGTPases in cell motility.