G protein small

Rittinger, K. et al. Crystal structure of a small G protein in complex with GTPase-activating protein rhoGAP. Nature 388 693-697, 1997. 

CBD Cdc42-binding domain Binding to the small G protein Cdc42... 

The membrane-associated small G proteins H-Ras and K-Ras have been studied with respect to their association with cytoplasmic leaflets. These two proteins have nearly identical structures and functions but different membrane anchors, membrane distributions and effector responses. Application of the FRAP method to fluorescent constructs of H-Ras and K-Ras revealed that only H-Ras in its guanosine 5 diphosphate (GDP)-bound form associates with cholesterol-dependent rafts [26]. 

The best characterized small G protein is the Ras family, a series of related proteins of =21 kDa 342... 

Rab is a family of small G proteins involved in membrane vesicle trafficking 343... 

Mammalian G proteins can be divided into two major categories heterotrimeric G proteins and small G proteins. This chapter reviews the types of G protein that exist in the nervous system and the ways in which they regulate signal transduction and other processes essential for brain function. 

Rab is a family of small G proteins involved in membrane vesicle trafficking. Mammalian tissues contain around 30 forms of Rab, which specifically associate with the various types of membrane vesicles and organelles that exist in cells [30,31]. Rab proteins, named originally as ras-related proteins in brain, are isoprenylated and associate with membranes, as do isoprenylated Ras and G protein y subunits. However, unlike these other G proteins, the GTP and GDP binding to Rab appears to regulate its association with membrane compartments. 

Cholera toxin catalyzes the ADP-ribosylation of a specific arginine residue in G and Gat. This covalent modification inhibits the intrinsic GTPase activity of these a subunits and thereby freezes them in their activated, or free, state (Fig. 19-1C). By this mechanism, cholera toxin stimulates adenylyl cyclase activity and photoreceptor transduction mechanisms. The ability of cholera toxin to ADP-ribosylate G may require the presence of a distinct protein, ADP-ribosylation factor (ARF). ARF, which is itself a small G protein (Table 19-2), also is ADP-ribosylated by cholera toxin. ARF is implicated in controlling membrane vesicle trafficking (see Ch. 9). 

A third type of bacterial toxin, diphtheria toxin, catalyzes the ADP-ribosylation of eukaryotic elongation factor (EFTU), a type of small G protein involved in protein synthesis (Table 19-2). The functional activity of the elongation factor is inhibitedby this reaction. Finally, a botulinum toxin ADP-ribosylates and disrupts the function of the small G protein Rho, which appears to be involved in assembly and rearrangement of the actin cytoskeleton (Table 19-2). These toxins maybe involved in neuropathy (see Ch. 36) and membrane trafficking (see Ch. 9). 

Of course, the critical importance of Ras and most other small G proteins in cell growth and differentiation is highlighted by the consideration, stated above, that several forms of these proteins are proto-oncogenes (see also... 

FIGURE 2 0-5 Activation of PLC-e by heterotrimeric (Gal2/i3, GI(Vy, GJ and small G protein (Ras, Rho and Rap) signaling pathways (see text for details). (Modified with permission from reference [11].) Note that Ras, activated via the mitogen-activated protein kinase (MAPK) pathway, may also activate PLCe. For details of the MAPK pathways and abbreviations, see Chapter 24. 

MAPK kinase (MAPKK). MAPK kinase itself is activated by phosphorylation by still another protein kinase, termed MAPK kinase kinase (MAPKKK). MAPK kinase kinase is activated upon interaction with a member of the Ras superfamily of small G proteins, which are bound to the plasma membrane (see Ch. 19). The exact mechanism of activation remains unknown, but it is believed that Ras and related proteins, in the activated GTP-bound form, can bind MAPK kinase kinase and thereby draw the kinase to the plasmalemma, where it is activated by as yet unknown factors, perhaps even an additional kinase, MAPK kinase kinase kinase (MAPKKKK). The mechanism governing the activation of Ras and related proteins by extracellular signals is quite complex and involves numerous Tinker proteins, for example She, Grb and Sos, that couple Ras to a variety of plasmalemma-associated growth factor-protein tyrosine kinase receptors (see Chs 20,24 and 27). 

A second family of MAPKs is referred to as stress-activated protein kinases (SAPKs) [3,14,15]. This includes JNKs, or Jun kinases, named originally for their phosphorylation of the transcription factor c-Jun. SAPKs were first identified in peripheral tissues on the basis of their activation in response to cellular forms of stress, which include X-ray irradiation and osmotic stress. More recently, they have been demonstrated to be activated in brain by several cytokines as well as by synaptic activity [16]. As shown in Figure 23-3, SAPKs are activated by SAPK kinases (SEKs), which are in turn activated by SEK kinases. The Ras-like small G proteins implicated in SEK kinase activation are Rac and Cdc-42. In this case, it appears that Rac/Cdc-42 triggers activation of SEK kinase by stimulating its phosphorylation by still another protein kinase termed p21-activated kinase (PAK). Thus, PAK can be considered a MAPK kinase kinase kinase, which is analogous to the cascade of protein kinases found in yeast (Fig. 23-4). 

The small G-proteins Ras and Rac Src-like tyrosine kinases Phospholipase Aj ... 

One of the major adaptors is the GRB2-SOS complex, which upon docking to the phosphorylated receptor, binds the small G protein Ras and activates it by GDP-GTP exchange in a manner analogous to the heterotrimeric G proteins. 

Over 30% of all human cancers have activating mutations of the gene encoding the small G protein Ras. 

Although farnesol did not affect the prenylation of small G-proteins [295], the derivatized forms of farnesol inhibited methyltransferase activity [296-299] and suppressed the prenylation of G-proteins [300]. 

Perillyl alcohol induced apoptosis and was more effective than perillaldehyde at inhibiting the proliferation of human carcinoma cell lines cultured in vitro [319]. Perillyl alcohol treatments suppressed cell growth [313-315], reduced cyclin D1 RNA and protein levels and prevented the formation of active cyclin D1 associated with kinase complexes in synchronous cells during the exit of GO and entry into the cell cycle [284, 316, 317]. In addition, perillyl alcohol treatment induced an increased association of p21 [316-318] with cyclin E-Gdk2 complexes, inhibited the activating phosphorylation of Gdk2 [312, 316, 318-320], initiated apoptosis [321-324] and suppressed small G-protein isoprenylation... 

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