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The Rho GTPase cycle

Rho proteins, such as Rac1, RhoA and Cdc42, are guanine nucleotide binding proteins that cycle between an inactive GDP-bound state and an active GTP-bound state.  The activity of Rho proteins is controlled by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs).  GEFs activate small GTPases by promoting the exchange of GDP for GTP, whereas GAPs enhance the intrinsic rate of hydrolysis of bound GTP for GDP, leading to inactivation. 

It is increasingly apparent that Rho GEFs do more than simply activate Rho molecules; several studies now point to their role in influencing the choice of biological response elicited by a given Rho protein.  GEFs have been shown to bind to effectors directly or to scaffold proteins that complex with components of effector pathways.  In our lab, we are using biochemical approaches to identify Rac and Rac GEF interacting proteins involved in different aspects of cellular transformation including malignant conversion (acquisition of invasiveness).

 

rho GTPase cycle

Figure 1 LegendThe Rho GTPase cycle. Rho-like GTPases cycle between an active GTP-bound and an inactive GDP-bound form. This is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Guanine nucleotide dissociation inhibitors (GDIs) inhibit nucleotide dissociation and control cycling of Rho GTPases between membrane and cytosol. Signals like growth factors, extracelullar matrix (ECM) or lysophosphatidic acid (LPA) are able to activate Rho-like GTPases. Active GTPases interact with effector molecules to elicit various cellular responses. Additionally GEFs could work as scaffold proteins by either binding directly to Rac effectors or other scaffold proteins that bind to effectors.