The Rho GTPases in Cancer

The Rho GTPases were first discovered due to their homology to Ras GTPase. Approximately 30% of human cancers harbor an activating mutation to Ras, and Ras mutations promote cell growth and survival. Due to their homology to Ras, great enthusiasm has ensued over the discovery of the Rho GTPases. It was thought that activating mutations, similar to what is seen in Ras, would be found in the Rho proteins and would account for a proportion of human cancers that did not harbor Ras mutations. After an intense survey of multiple human cancer specimens, no evidence of activating mutations were found. Instead, overexpression of Rho proteins and aberrant activation were found to be common. Aberrant activation of Rho GTPase is found to be caused by alterations in the activity of upstream Rho-regulatory proteins. Since their discovery, 22 human Rho proteins have been identified and several have been shown to be involved in cancer progression. In contrast to Ras and its closely related members, Rho proteins act as dynamic switches to alter the actin cytoskeleton. Because of this, these proteins regulate nearly all aspects of cell physiology including growth, polarity and migration. Thus, they are very important molecules in cancer biology and constitute potential and desirable therapeutic targets.