Spatiotemporal dynamics of RhoA activity in migrating cells

Abstract

Rho family GTPases regulate the actin and adhesion dynamics that control cell migration. Current models postulate that Rac promotes membrane protrusion at the leading edge and that RhoA regulates contractility in the cell body. However, there is evidence that RhoA also regulates membrane protrusion. Here we use a fluorescent biosensor, based on a novel design preserving reversible membrane interactions, to visualize the spatiotemporal dynamics of RhoA activity during cell migration. In randomly migrating cells, RhoA activity is concentrated in a sharp band directly at the edge of protrusions. It is observed sporadically in retracting tails, and is low in the cell body. RhoA activity is also associated with peripheral ruffles and pinocytic vesicles, but not with dorsal ruffles induced by platelet-derived growth factor (PDGF). In contrast to randomly migrating cells, PDGF-induced membrane protrusions have low RhoA activity, potentially because PDGF strongly activates Rac, which has previously been shown to antagonize RhoA activity. Our data therefore show that different extracellular cues induce distinct patterns of RhoA signalling during membrane protrusion.

The effects of modifying RhoA and Rac1 activities on heterotypic contact inhibition of locomotion

“…All three proteins are involved in actin polymerization and have been shown to be localized in the cell leading edge during protrusion formation [18][19][20][21][22]. We found both increasing (V12Rac1) and lowering (N17Rac1) activity resulted in defective heterotypic CIL.…”

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

“…Indeed, inhibition of ROCK activity counteracted the effect of extracellular Ab, preventing growth cone collapse and suggesting the possibility of a protective role of ROCK inhibitors in AD. The initial functional characterization of the members of the Ras superfamily of GTPases established actin cytoskeleton as their main target 37 , and later those observations were extended to reveal their function in the regulation of MT organization 38 . Growth cone movement is necessary for elongation and pathfinding of developing neurons.…”

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

“…RhoA might play a role in focal adhesion disassembly by recruiting c-Src to focal adhesions through activation of mDia [80]. Further, elevated RhoA activity in the leading edge [81] might determine mDia regulated stabilization of microtubules [57] that are required for targeted disassembly of focal adhesions [82] (see below) and actinmediated recruitment of c-Src to membranes and focal adhesions [80].…”