The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic kingdoms, including yeasts and some plants.
In a 1998 review article, Alan Hall compiled evidence showing that not only do fibroblasts form processes upon Rho activation, but so do virtually all eukaryotic cells.
[11] The Rho family of GTPases belong to the Ras superfamily of proteins, which consists of over 150 varieties in mammals.
When a Rho protein activated in this manner is expressed in 3T3 cells, morphological changes such as contractions and filopodia formation ensue.
[11] One method of maintaining the spatial zones of activation is through anchoring to the actin cytoskeleton, keeping the membrane-bound protein from diffusing away from the region where it is most needed.
[11] Another method of maintenance is through the formation of a large complex that is resistant to diffusion and more rigidly bound to the membrane than the Rho itself.
[11] In addition to the formation of lamellipodia and filopodia, intracellular concentration and cross-talk between different Rho proteins drives the extensions and contractions that cause cellular locomotion.
Sakumura et al. proposed a model based on differential equations that helps explain the activity of Rho proteins and their relationship to motion.
The paper concludes by showing that the model predicts that there are a few threshold concentrations that cause interesting effects on the activity of the cell.
[20] Studies in fibroblasts indicate positive feedback between Cdc42 activity and H+ efflux by the Na-H exchanger isoform 1 (NHE1) at the leading edge of migrating cells.
NHE1-mediated H+ efflux is required for guanine nucleotide exchange factor (GEF)-catalyzed GTP binding to Cdc42, suggesting a mechanism for regulation of polarity by this small GTPase in migrating cells.
[23] Because of their implications in cellular motility and shape, Rho proteins became a clear target in the study of the growth cones that form during axonal generation and regeneration in the nervous system.
[citation needed] These natural efforts include the formation of a growth cone at the proximal end of an injured axon.
This is partly due to the exogenous Rho proteins driving cellular locomotion despite the extracellular cues promoting apoptosis and growth cone collapse.
After the cloning of various genes implicated in X-linked mental retardation, three genes that have effects on Rho signaling were identified, including oligophrenin-1 (a GAP protein that stimulates GTPase activity of Rac1, Cdc42, and RhoA), PAK3 (involved with the effects of Rac and Cdc42 on the actin cytoskeleton) and αPIX (a GEF that helps activate Rac1 and Cdc42).
Overexpression of RhoA, RhoB, RhoC, Rac1, Rac2, Rac3, RhoE, RhoG, RhoH, and Cdc42 has been shown in multiple types of cancer.
[12] This increased presence of so many signaling molecules implies that these proteins promote the cellular functions that become overly active in cancerous cells.
Rho proteins are very tightly controlled by a wide variety of sources, and over 60 activators and 70 inactivators have been identified.
[17] Multiple GAPs, GDIs, and GEFs have been shown to undergo overexpression, downregulation, or mutation in different types of cancer.
After natural apoptosis is suppressed, abnormal tumor growth can be observed through the loss of polarity in which Rho proteins play an integral role.
[12] Finally, after inhibition of apoptosis, cell polarity and adhesion molecules, the cancerous mass is free to metastasize and spread to other regions of the body.