RERG: Human Ras-like estrogen regulated growth inhibitor
PDB Code: 2ATV
Cells respond in many ways to environmental changes including altering gene expression, physically moving locations, changes to cell-cell interactions, differentiation and even altering their life spans. This is achieved through a signalling network that consists of several signalling pathways. The network receives multiple signals, interprets the signals, amplified and then transmits the signals. One of the best characterised signalling pathways involves the ras GTPase family. The importance of this family of small GTPases to human health was first recognised through the identification of the human H-Ras, N-Ras and K-Ras genes as being oncogenic.
Generally, the small GTPase family of proteins exist in two forms: an inactive GDP bound form and an active GTP bound state. An increased conversion of the active to inactive state occurs through the interaction of GTPase activating proteins (GAPs) while guanine nucleotide exchange factors (GEFs) enhances the exchange of GDP for GTP. The mutant forms of the H-, N- and K-Ras GTPases knocks out the hydrolytic activity of the enzymes hence the signalling pathway is always on as the GTPase is in the GTP bound active state ultimately leading to uncontrolled cell proliferation.
Another feature that is common to most small GTPase is the localisation of the proteins to the membrane. This interaction with the membrane occurs mainly at a C-terminal site on the protein via lipid modification.
Not all small GTPases are onocogenic. A study to identify high level expressing proteins that correlate with a positive outcome for patients with breast tumors identified one as a small GTPase. This enzyme was later characterised as a Ras-related, Estrogen-Regulated GTPase (RERG) and shown to slow the rate of tumor cell proliferation. The lack of a lipid modification motif on the C-terminus of RERG corresponds with its mainly cytosolic cellular distribution.
As RERG is a small GTPase that functions as a breast tumor suppressor protein, it along with the proteins involved in its unresolved signalling pathway, are potentially significant pharmaceutical targets against this disease.
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