MoBio Ras and Other Small G Proteins Chapter 6

Small G proteins are monomeric G proteins with molecular weight of 20-40 kDa. Like heterotrimeric G proteins, their activity depends on the binding of GTP. More than 100 small G proteins have been identified. They are classified into five families: Ras, Rho, Rab, Ran and Arf (Table).

Ras

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Figure 6-E-3. Cycling of the Ras protein between active and inactive states. Like other G proteins, Ras can switch between GTP-bound and GDP-bound states. Transition from the GDP-bound to the GTP-bound state is catalyzed by guanine nucleotide exchange factor (GEF) which induces exchange between the bound GDP and the cellular GTP. The reverse transition is catalyzed by a GTPase-activating protein (GAP) which induces hydrolysis of the bound GTP.

Ras and cancer

Mutations of the Ras proto-oncogenes (H-Ras, N-Ras, K-Ras) are found in about 25% of all human tumors. Most of these mutations result in the abrogation of the normal GTPase activity of Ras. The Ras mutants can still bind to GAP, but cannot catalyze GTP hydrolysis. As a result, they remain in the active state for a much longer period. Malignant transformation may arise from the unregulated stimulation of Ras signaling pathways, which either stimulate cell growth or inhibit apoptosis.