The activation of the monomeric GTPases Rho, Rac, and Cdc42 occurs through an exchange of GTP for a tightly bound GDP molecule, catalyzed by guanine nucleotide exchange factors (GEFs). Of the many GEFs that have been identified in the human genome, some are specific for an individual Rho family GTPase, whereas others seem to act on multiple family members. Different GEFs are restricted to specific tissues and even specific subcellular locations, and they are sensitive to distinct kinds of regulatory inputs. GEFs can be activated by extracellular cues through cell-surface receptors, or in response to intracellular signals. GEFs may also act as scaffolds that direct GTPases to downstream effectors. Interestingly, several of the Rho family GEFs associate with the growing ends of microtubules by binding to one of the +TIPs. This provides a connection between the dynamics of the microtubule cytoskeleton and the large-scale organization of the actin cytoskeleton; such a connection is important for the overall integration of cell shape and movement.
External Signals Can Dictate the Direction of Cell Migration
Chemotaxis is the movement of a cell toward or away from a source of some diffusible chemical. These external signals act through Rho family proteins to set up large-scale cell polarity by influencing the organization of the cell motility apparatus. One well-studied example is the chemotactic movement of a class of white blood cells, called neutrophils, toward a source of bacterial infection. Receptor proteins on the surface of neutrophils enable them to detect very low concentrations of N-formylated peptides that are derived from bacterial proteins (only prokaryotes begin protein synthesis with N-formylmethionine). Using these receptors, neutrophils are guided to bacterial targets by their ability to detect a difference of only 1% in the concentration of these diffusible peptides on one side of the cell versus the other (Figure 16–86A).
In this case, and in the chemotaxis of Dictyostelium amoebae toward a source of cyclic AMP, binding of the chemoattractant to its G-protein-coupled receptor activates phosphoinositide 3-kinases (PI3Ks) (see Figure 15–52), which generate a signaling molecule [PI(3,4,5)P3] that in turn activates the Rac GTPase. Rac