Rho/Rac proteins

The Ras GTP-mediated activation of P13-kinase links the Ras pathway with fimcti-ons of the Rho/Rac proteins. Members of this protein family within the Ras superfamily control formation of the cytoskeleton. The exact nature of the linkage with the Ras/PI3-kinase signal conduction to the Rac proteins is unknown. There is evidence that the product of the P13-kinase, Ptd-lns(3,4,5)P3, binds to the PH domain of the Vav protein and activates the latter. The Vav protein functions as a nucleotide exchange factor for the Rac GTPase (Han et al., 1998). The observation that activation of the Ras pathway is accompanied by reorganization of the cytoskeleton is in agreement with these findings. 

There are also links to other members of the Ras superfamily, such as the Ral protein and the Rho/Rac proteins. The latter are involved in reorganization of the actin cytoskeleton. Transformation of cells with oncogenic Ras mutants is associated with reorganization of the actin cytoskeleton and it is assumed that this effect is due to coupling of the Ras pathways with the fimction of Rho/Rac proteins. 

Activation of MEK kinases occurs particularly via proteins of the Ras superfamUy (p21-Ras, Rho/Rac proteins). However, other pathways for activation of MEK kinases, e.g., via other protein kinases such as protein kinase C or PAK (p21 activated kinase) (review Marshall, 1995 Robinson and Cobb, 1997) have also been reported. 

The Ras GTP-mediated activation of PI3-kinase links the Ras pathway with functions of the Rho/Rac proteins. Members of this protein family within the Ras super-... 

Members of this family of small GTPases have members of the family of p21-acti-vated protein kinases (PAKs) as effectors, which phosphorylate and activate MAP3K proteins. Furthermore, the MEKK1 protein has been identifed as a direct effector of GTP-activated Rho/Rac proteins. 

Neurotrophins (NGF brain-derived neurotrophic factor, BDNF neurotrophin-3, NT-3 NT-4 NT-6) are important regulators of neural survival, development, function, and plasticity of the vertebrate nervous system [1]. Neurotrophins generally function as noncovalently associated homodimers. They activate two different classes of receptors, through which signaling pathways can be activated, including those mediated by Ras and members of the cdc42/rac/rho G protein families, MAP kinase, PI-3 kinase, and Jun kinase cascades. 

There is no doubt that each of these multiple actions is important and of great interest, but I had to make a quite arbitrary choice in selecting for discussion only one of the many functions of monomeric G proteins in the control of fundamental cellular processes. I have chosen the role of the Rho/Rac/Cdc42 GTPases in the regulation of cell proliferation, mainly because it gave me an opportunity to introduce cell-cell interactions and the role of the cytoskeleton. 

Rac proteins (Racl,2), which are also members of the Rho subfamily, are involved in membrane ruffling and lamellipodia formation induced by growth factors (Ridley et al., 1992 Hall, 1994), and it has also been suggested that they are important for Ras-induced transformation (Qiu et al., 1995). Moreover, Rac proteins control NADPH oxidase (Abo et al., 1991 Bokoch, 1994), and may have a role in phospholipase A2 regulation (Peppelenbosch et al., 1995). Cdc42, another member of the Rho family, which occurs in at least two iso-... 

Toxin A glucosylates the identical substrate proteins (Rho, Rac, Cdc42) that are glucosylated by toxin B. Thus, the glucosylation reaction can also be performed with toxin A. However, the toxin A concentration has to be 10(ig/ml (instead of 1 (ig/ml for toxin B). 

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