The three main ras effectors raf kinase ral gefs and

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Unformatted text preview: three main RAS effectors, RAF kinase, RAL-GEFs, and PI3K, bind the same region of RAS-GTP, the 32-40 domain. All three effectors increase their in vivo activity after RAS binding (17) (Figure 2). 9 Figure 3. RAS is a GTPase, which is activated by GDP to GTP ex change. Active RAS is able to stimulate many effector proteins. Thes e include Rho GAP, GEFs such as RalGDS, and a number of protein kinases s uch as PI3 K, PKC, RAF, MEK, and ERK. RAS-RAF-ERK signaling The best known RAS stimulated pathway, which has been most directly linked to growth promotion activities, starts with activation of the RAF family of serinethreonine kinase. There are three members of the RAF class: ARAF, BRAF and CRAF. Recent studies suggest that RAS interacts with the amino terminal portion of RAF located in the cytoplasm in a complex with 14-3-3 protein, which is an essential cofactor of RAF kinase activity(18). This interaction causes a RAF conformational change unmasking one or more residues of phosphorylation and stabilizing a new catalytically active RAF conformation. After these conformational changes, RAF is anchored in the plasma membrane. The RAF-RAS binding is transitory and once attached to plasma membrane, RAF activity becomes independent of RAS and is no longer influenced by dominant negative RAS mutations. The phosphorylated RAF activates a series of kinases in a cascade that by amplifying low level cell membrane signals, modulate the activity of several cytoplasmic and nuclear factors (19). Finally, the signals transmitted to the nucleus determine the activation of transcriptional factors, such as the members of Ets family (20). These transcriptional factors 10 influence the expression of specific genes encoding proteins involved in the control of cellular proliferation and/or differentiation (17) (Figure 2). RAS-PI3K-AKT signaling Another well-characterized RAS effector is PI3K, which has a role in both cell proliferation and survival. PI3-kinases are lipid kinases that phosphorylate the 3'-OH position of inositol phospholipids. RAS-GTP...
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