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Thus the Ral signaling appears to regulate vesicle trafficking, cytoskeletal organization, gene expression, and cell transformation. The GAP proteins for RalA were characterized and partially purified 48 , ; however, the molecular cloning of these proteins has not yet been achieved. R-Ras has been shown to be involved in multiple biological functions: the ability to transform NIH 3T3 cells, the promotion of cell adhesion, and the regulation of apoptotic response in hematopoietic cells , , , TC21 has a highly oncogenic potential and is found mutated in some human tumors and overexpressed in breast cancer 37 , 94 , As to the activation of Raf proteins by TC21, it is controversial , Recently, new members of the Ras family, Rit and Rin, have been identified by an expression cloning screen Rit is ubiquitously expressed, whereas Rin is expressed only in neural tissue.

A unique feature of their structures is that they lack a known recognition signal for COOH-terminal prenylation.

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Nonetheless, both proteins localize on the plasma membrane, probably through a COOH-terminal cluster of basic amino acids. Rin binds calmodulin through a COOH-terminal motif, suggesting that Rin may be involved in calcium-mediated signaling in neurons Rad is another member of Ras-like proteins that has originally been isolated as a gene overexpressed in the skeletal muscle of humans with type II diabetes The distinct structural features of this family include the G3 GTP-binding motif, extensive NH 2 - and COOH-terminal extensions beyond the Ras-related domain, and a motif that determines membrane association Rheb, another Ras protein-related molecule, has been isolated by differential cloning techniques to identify genes that are rapidly induced in brain neurons by synaptic activity Expression of Rheb is rapidly and transiently induced in hippocampal granule cells by seizures and by NMDA-dependent synaptic activity The amino acid sequence of Rheb is most closely homologous to yeast Ras1 and human Rap2.

In the developing brain, Rheb mRNA is expressed at relatively high levels. Its close homology with Ras proteins and its rapid inducibility by receptor-dependent synaptic activity suggest that Rheb may play an important role in long-term activity-dependent neuronal responses The mammalian Rho family consists of at least 14 distinct members as shown in Table 1 and Figure 1. The function of the Rho family was first demonstrated in yeast 5 , 45 , In mammals, the function of Rac proteins was the first to be clarified. GTP-Rac1, in addition to two other cytosolic proteins, p47phox and p67phox, were shown to be required for the activation of NADPH oxidase of phagocytic cells 1 , 2 , 18 , , , Then, the function of mammalian Rho proteins was elucidated by use of an exoenzyme of Clostridium botulinum , named C3, that specifically ADP-ribosylates Rho proteins 6 , , C3 ADP-ribosylates an amino acid Asn in the effector region of RhoA and inhibits its function by preventing interaction with downstream effectors By the use of C3, Rho proteins were first suggested to be involved in cytoskeletal control 97 , In contrast, Rac and Cdc42 proteins regulate formation of lamellipodia and filopodia, respectively , , Evidence has also accumulated that they may play additional roles in gene expression , , , , , Reorganization of the actin cytoskeleton plays crucial roles in many cellular functions such as cell shape change, cell motility, cell adhesion, and cytokinesis.

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The actin cytoskeleton is composed of actin filaments and many specialized actin-binding proteins , , Filamentous actin is generally organized into a number of discrete structures Fig. They are found primarily in motile cells and neuronal growth cones. It is important, therefore, that the polymerization and depolymerization of cortical actin be tightly regulated. Rho proteins regulate stress fiber formation , , while Rac proteins regulate ruffling and lamellipodia formation , and Cdc42 regulates filopodium formation , A : mode of action of Rho proteins.

B : mode of action of Rac proteins. C : mode of action of Cdc Rho, Rho proteins; Rac, Rac proteins. However, they are further regulated by another class of regulator, GDIs , , , , The GTP-bound form then interacts with the downstream effector s. Some amount of the GDP-bound form may be associated with membranes, and it may be converted to the GTP-bound form and exert its function on the membrane. In this case, GDIs would not be essential for their cyclical activation and inactivation.

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Most GEPs have been isolated as oncogenes. The GEPs thus far identified share a common motif, designated the Dbl-homology DH domain, for which the Dbl oncogene product is the prototype Lbc, for example, and more recently discovered oncoproteins Lfc and Lsc are specific for Rho proteins , , whereas FGD1 and frabin are specific for Cdc42 , , Some GEPs, such as Dbl, prefer the lipid-modified form of the substrate small G proteins to the lipid-unmodified ones In addition to the PH and DH domains, many GEPs have other domains that are commonly found in signaling molecules, such as the SH2 domain for Vav or the SH3 domain for Vav and Dbs, suggesting that they may have additional functions 93 , , , These findings have provided a new model for a signaling pathway for Rho proteins from membrane receptors.

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Recently, SHP-2, a protein tyrosine phosphatase containing SH2 domains, has been demonstrated to suppress the activity of Vav2 and consequently to reduce the Rho's ability to form stress fibers and focal adhesions In addition to the PH domain, frabin has an actin-binding domain at its NH 2 -terminal region The actin-binding domain in addition to the DH and first PH domains is essential for the filopodium formation mediated by frabin through Cdc42 , Frabin furthermore induces lamellipoidum formation through indirect activation of Rac The first GAP protein specific for Rho proteins was biochemically purified from human spleen and bovine adrenal gland , , Although some of these proteins exhibit GAP activity for several small G proteins in cell-free assay systems, their substrate specificities in vivo appear to be more restricted.

A role for p Rho GAP in regulating Rho protein function in cells undergoing cytoskeletal rearrangements has been suggested 95 , , but it is not known whether this effect is induced by p Rho GAP as a downstream effector of Rho proteins. Table 2. The mode of action of Rho proteins in cell scattering remains to be clarified, but the Rho protein-regulated assembly and disassembly of stress fibers and focal adhesions have been suggested to be, at least in part, involved in this process , , , It is not known how inactivation by GAPs is induced.

In one case, integrin-induced formation of stress fibers inhibits Rho protein activation as part of a feedback inhibition system Based on these properties of Rho GDI, it has been proposed that Rho GDI is involved not only in the regulation of the activation of Rho proteins but also in their translocation between the cytosol and the membrane , , In addition, the geranylgeranyl moiety of Cdc42 inserts into a hydrophobic pocket within the immunoglobulin-like domain of the GDI molecule, keeping GDP-Cdc42 in the cytosol and permitting the dissociation of GDP-Cdc42 from membranes.

ERM is translocated to the plasma membrane probably through the interaction with the cytoplasmic domain of integral plasma membrane proteins such as CD44, providing the F-actin binding sites. These findings suggest that the activation of Rho proteins is regulated in a temporally and spatially dynamic manner and is distinct from that of Ras proteins, which appears to be regulated in a unidirectional manner.

These mice are initially viable, but they develop massive proteinuria mimicking nephrotic syndrome in humans, leading to death due to renal failure within a year. Histologically, degeneration of tubular epithelial cells and dilatation of distal and collecting tubules are readily detected in the kidneys.

Thus these two lines of evidence suggest that Rho GDIs play physiologically important roles. Mammalian Rho proteins are required for many actin cytoskeleton-dependent cellular processes, such as platelet aggregation, lymphocyte and fibroblast adhesion, cell motility, contraction, and cytokinesis , The mode of action of Rho proteins was first clarified for Rho1 in the yeast budding process. Pkc1, a yeast homolog of mammalian protein kinase C, was first shown to be a downstream effector of Rho1 , This MAP kinase cascade regulates expression of the genes necessary for cell wall integrity.

Bni1 is another effector of Rho1 Kamei and Y. Takai, unpublished observations , and GTP-Cdc42 Bni1 has two domains, named formin homology FH 1 and FH2 domains, which are found in a variety of proteins involved in cytoskeletal rearrangement needed to achieve cell polarity and cytokinesis Bni1 binds the actin monomer-binding protein profilin via its FH1 domain to regulate reorganization of the actin cytoskeleton , Furthermore, Bni1 binds Aip3 Bud6 , another actin-binding protein 15 , and elongation factor 2, which is known to stimulate actin polymerization , suggesting that Bni1 is the downstream effector of Rho1 that directly regulates reorganization of the actin cytoskeleton.

More recently, Bni1 has also been shown to participate in microtubule function, since disruption of BNI1 causes defects in spindle orientation , Kar9 localization , and growth defect together with mutation either PAC1 and NIP , whose gene products are implicated in microtubule function This series of experiments has established that Rho proteins regulate complicated cell functions through multiple effectors in a cooperative manner. Another protein having FH domains has also been found in yeast and named Bnr1 This protein serves as an effector of Rho4 and binds both profilin and Aip3 Bud6 , indicating that Rho4 regulates the actin cytoskeleton at least though Bnr1.

Hence, it has been assumed that Rho2 has redundant functions with Rho1, although several lines of evidence suggest Rho2-specific functions , Rho3 and Rho4 are implicated in polarized growth presumably through regulating the actin cytoskeleton via their interactions with Bni1 and Bnr1 , a. Moreover, it has been shown that Rho3 interacts with Myo2 type V myosin and Exo70 a component of the exocyst, a multiprotein complex which is involved in exocytosis , suggesting the involvement of Rho3 in the polarized secretion.


Small GTP-Binding Proteins

Numerous downstream effectors of mammalian Rho proteins have been identified Table 3. The activity of this protein kinase is stimulated by GTP-Rho proteins. Of these substrates, myosin light-chain phosphatase appears to be a physiological substrate Subsequently, myosin light-chain phosphatase has been shown to be a downstream effector of Rho proteins , The physiological relevance of the phosphorylation of other substrate proteins, including moesin, is also controversial.

Overexpression of mDia induces weak formation of stress fibers without affecting the formation of focal adhesions , Cofilin exhibits actin-depolymerizing activity that is inhibited as a result of its phosphorylation by LIM kinase , Table 3. Citron contains a protein kinase domain that is related to ROCK. Citron kinase localizes to the cleavage furrow and midbody of cultured cells Overexpression of citron mutants results in the production of multinucleate cells, and a kinase-active mutant causes abnormal contraction during cytokinesis, suggesting that citron kinase is involved in the Rho protein-regulated cytokinesis In fibroblasts, Rac proteins regulate formation of lamellipodia and membrane ruffles and subsequent stress fiber formation In contrast, Cdc42 plays a key role in the formation of filopodia at the cell periphery followed by the formation of lamellipodia and membrane ruffles , Cdc42 may play a role in the polymerization of both actin and microtubules toward antigen-presenting cells Furthermore, the involvement of Cdc42 in the control of cytokinesis in HeLa cells and Xenopus embryos has been reported , To date, several potential effectors of Cdc42 and Rac proteins have been identified Table 3.

Several of these proteins are common effectors for both Rac and Cdc42 proteins. Homologs of the mammalian PAKs have been identified in S. Drosophila PAK1 also plays a role in dorsal closure Most recently, Drosophila Trio, a GEP for Rac proteins, has been shown to play an important role in axon guidance 32 , 43 , , One of the two Trio GEP domains is critical in photoreceptor axon guidance Thus Trio regulates Rac proteins, which subsequently activates PAK, linking guidance receptors to the growth cone cytoskeleton However, in mammalian cells, the role of PAKs remains unclear Fig.

Expression of a mutant form of Rac or Cdc42 protein that is unable to bind and activate PAKs can still induce the formation of membrane ruffles and lamellipodia , , indicating that PAKs are not essential for the Rac protein-elicited membrane ruffling and lamellipodium formation or for the Cdctriggered filopodium formation. Wiskott-Aldrich syndrome protein WASP , which is only expressed in hematopoietic cells, was originally identified as a protein mutated in patients with Wiskott-Aldrich syndrome 31 , Arf6 and POR1 function on distinct signaling pathways to mediate cytoskeletal reorganization induced by Rac proteins Fig.

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IQGAP has been shown to be localized to cell-cell adhesion sites It has been suggested that activated Cdc42 blocks the ability of IQGAP to inhibit asse bly of a cadherin-catenin complex and thereby promotes formation of adherens junctions , but this model has not yet been substantiated. In addition, no apparent abnormality is observed in the formation of adherens junctions in the IQGAP1-deficient mice Although a number of potential Rho family effectors have been identified, a major goal for the future will be to determine the physiological roles of these proteins in Rho family-mediated cytoskeletal rearrangement.

Genetic analysis of dorsal closure in Drosophila also supports a role for Rac proteins in JNK regulation This observation may be related to the fact that Rac proteins regulate an NADPH oxidase enzyme complex in phagocytes to produce superoxide as described earlier 1 , 2 , 18 , , , Cytoskeletal rearrangements are closely coupled to the onset of phagocytosis.

Two distinct mechanisms for the phagocytic response have recently been defined 8 , In type II phagocytosis, particles sink into actin-lined investigations in the plasma membrane; here, internalization is dependent on RhoA There are morphological similarities between these processes and the invasion of mammalian cells by certain pathogenic bacteria. Shigella invasion starts with actin nucleation and Rho protein-induced actin polymerization 4 , This is followed by continued actin polymerization around membrane-bound protrusions that fold over the bacterium and coalesce to engulf it.

The complete inhibition of Shigella -induced membrane folding by C3 suggests that actin polymerization is essential for the generation of the surface extensions 4 , Interestingly, Cdc42 has been shown to play a direct role in Salmonella internalization and in Shigella flexneri motility Expression of a dominant active mutant of RhoA causes an increase in clathrin-independent endocytosis in Xenopus oocytes In Swiss 3T3 cells, expression of a dominant active mutant of Rac proteins stimulates pinocytosis , and the pinocytic vesicles are coated with the Rac signaling partner PAK1 However, expression of a dominant active Rac protein has no effect on pinocytosis in baby hamster kidney cells ; thus the role of Rac proteins in pinocytosis is still unclear.

RhoD and RhoB are localized to endocytic vesicles, suggesting that they might perform roles in the regulation of intracellular trafficking , For instance, the Drosophila homologs of Rac1, Rac2, and Cdc42, namely, DRac1, DRac2, and DCdc42, respectively, are highly expressed in the nervous system and in the mesoderm during development, respectively , Particularly, the inhibition of axonal outgrowth induced by a dominant active or dominant negative mutant of DRac1 is due to different cytoskeletal defects in developing neurons, suggesting that cyclical activation and inactivation of DRac1 is crucial for axonal development , In addition, expression of a dominant active mutant of DCdc42, DCdc42V12, in the neurons of fly embryos results in a similar but qualitatively different effect on neuronal development, compared with DRac1V12 In contrast, in chick dorsal root ganglion neurons, Rho proteins induce neurite outgrowth, while an activated mutant of Rac proteins increases the proportion of collapsed growth cones DRac1 and DCdc42 have also been implicated in muscle differentiation , Finally, little is known at present about the role of Rho proteins in neuronal and muscle development.

Rab proteins exist in all eukaryotic cells and form the largest branch of the small G protein superfamily , , , , , The yeast S. In mammalian cells, over 50 Rab proteins including isoforms are known , , , , Evidence that Rab proteins regulate intracellular vesicle trafficking was first obtained genetically in the yeast S.