Disease relevance of CDC42

• Moreover, we report that Salmonella SptP can act as a GAP for Cdc42 in S. cerevisiae, down-regulating MAPK-mediated signaling [1].
• Isolation of mutations in the Drosophila homologues of the human Neurofibromatosis 2 and yeast CDC42 genes using a simple and efficient reverse-genetic method [2].
• Interestingly, expression of membrane-targeted Far1p causes toxicity, most likely by activating Cdc42p uniformly at the cell cortex [3].

Psychiatry related information on CDC42

• Analysis using this assay further demonstrated that the motor activity of these myosins is required for the polymerization step, and that actin polymerization depends on phosphorylation of myosin motor domain by p21-activated kinases (PAKs), downstream effectors of the small guanosine triphosphatase, Cdc42p [4].

High impact information on CDC42

• In the organization of the bud site or of the site in which a mating projection appears, Cdc42, its activator Cdc24, and its negative regulators play a fundamental role [5].
• In the absence of Cdc42 or Cdc24, the actin cytoskeleton does not become organized and budding does not take place [5].
• The Ras-related GTP-binding protein Cdc42 is implicated in a variety of biological activities including the establishment of cell polarity in yeast, the regulation of cell morphology, motility and cell-cycle progression in mammalian cells and the induction of malignant transformation [6].
• We identified a Cdc42 mutant (Cdc42F28L) which binds GTP in the absence of a guanine nucleotide exchange factor, but still hydrolyses GTP with a turnover number identical to that for wild-type Cdc42 [6].
• The polarization of yeast cells shares many features with that of these more complex examples, including regulation by both intrinsic and extrinsic cues, conserved regulatory molecules such as Cdc42 GTPase, and asymmetry of the cytoskeleton as its centerpiece [7].

Biological context of CDC42

• Temperature-sensitive cells with mutations of the CDC24 and CDC42 genes, which are incapable of budding and of generating cell polarity at the restrictive temperature, are also unable to mate [8].
• Moreover, the temperature-sensitive growth phenotype of deltarom2 was suppressed by overexpression of RHO1 or RHO2, but not of CDC42 [9].
• TFS1 maps to a previously undefined locus on chromosome XII between RDN1 and CDC42 [10].
• Bni1p, a yeast formin linking cdc42p and the actin cytoskeleton during polarized morphogenesis [11].
• Gic1p and Gic2p colocalize with Cdc42p as cell polarity is established during the cell cycle and during mating in response to pheromones [12].

Anatomical context of CDC42

• In some strains, the ability of CDC42 to serve as a multicopy suppressor of the Ts- growth defect of deltabem4 cells required co-overexpression of Rho1p, which is an essential Rho-type GTPase necessary for cell wall integrity [13].
• For CDC42 controlled bud assembly in yeast, the components of the plasma-membrane complex are not so clear [14].
• Incorporation of the available data on rac in neutrophils, CDC42 in yeast, and rho in fibroblasts suggests a general model for the function of rho-like GTPase (Figure 1) [14].
• The AgCDC42 and AgCDC24 genes can both complement conditional mutations in the S. cerevisiae CDC42 and CDC24 genes and both proteins are required for the establishment of actin polarization in A. gossypii germ cells [15].
• Bni1p may function as a Cdc42p target that links the pheromone response pathway to the actin cytoskeleton [11].

Associations of CDC42 with chemical compounds

• Actin incorporation in the bud can be stimulated by treating the permeabilized cells with GTP-gamma S, and, significantly, the stimulatory effect is eliminated by a mutation in CDC42, a gene that encodes a Rho-like GTP-binding protein required for bud formation [16].
• Ste20/PAK serine/threonine protein kinases have been suggested as playing essential roles in cell signalling and morphogenesis as potential targets of Cdc42 and Rac GTPases [17].
• Cdc24p is the guanine-nucleotide exchange factor for the Cdc42p GTPase, which controls cell polarity in Saccharomyces cerevisiae [18].
• We have analyzed the effects of three CDC42 mutations (Gly to Val-12, Gln to Leu-61, and Asp to Ala-118) in the putative GTP-binding and hydrolysis domains and one mutation (Cys to Ser-188) in the putative isoprenylation site [19].
• The Pak1 protein autophosphorylates on serine residues and preferentially binds to activated Cdc42p both in vitro and in vivo [20].

Physical interactions of CDC42

• Novel Cdc42-binding proteins Gic1 and Gic2 control cell polarity in yeast [12].
• We also show that Cdc42p coimmunoprecipitated with Rsr1p/Bud1p from yeast extracts [21].
• The yeast IQGAP homologue, designated Iqg1p, displays a two-hybrid interaction with activated Cdc42p and coimmunoprecipitates with actin filaments [22].
• Cla4 is involved in budding and cytokinesis and interacts with Cdc42, a GTPase required for polarized cell growth [23].
• This function of Ste20 in the HOG pathway requires binding of the small GTPase Cdc42 [24].

Regulatory relationships of CDC42

• These results suggest that Cdc42 is closely involved in regulating actin assembly during polarized cell growth [16].
• However, one of the other genes that was isolated by virtue of its ability to suppress cdc24 can also suppress cdc42 [25].
• Cla4p kinase was activated in vivo by the GTP-bound form of Cdc42p [26].
• Elevated levels of STE20 and BEM1 are capable of suppressing a temperature-sensitive mutation in CDC42 [27].
• RA domain function can be replaced by the nine C-terminal, plasma membrane-targeting residues (KKSKKCAIL) of Cdc42, and membrane-targeted Ste50 also suppresses the signaling deficiency of cdc42 alleles specifically defective in invasive growth [28].
• We show that Bem1p promotes symmetry breaking by assembling a complex in which both a Cdc42p-directed guanine nucleotide exchange factor (GEF) and a Cdc42p effector p21-activated kinase (PAK) associate with Bem1p [29].

Other interactions of CDC42

• Therefore, the inability of cdc24 and cdc42 mutants to mate has been presumed to be due to a requirement for generation of cell polarity and related morphogenetic events during conjugation [8].
• Adaptor functions of Cdc42, Ste50, and Sho1 in the yeast osmoregulatory HOG MAPK pathway [30].
• CDC42 and CDC43, two additional genes involved in budding and the establishment of cell polarity in the yeast Saccharomyces cerevisiae [31].
• One of these proved to be CDC42, which has previously been shown to be a member of the rho (ras-homologous) family of genes, and a second is a newly identified ras-related gene that we named RSR1 [25].
• Ste20, which phosphorylates Ste11 to initiate signaling, is activated by binding to Cdc42 GTPase (membrane anchored via its C-terminal geranylgeranylation) [28].

Analytical, diagnostic and therapeutic context of CDC42

• Molecular cloning of the gene for the human placental GTP-binding protein Gp (G25K): identification of this GTP-binding protein as the human homolog of the yeast cell-division-cycle protein CDC42 [32].
• Each protein contains a CRIB (Cdc42/Rac-interactive binding) motif and each interacts in the two-hybrid assay with the GTP-bound form of the Rho-type Cdc42 GTPase, a key regulator of polarized growth in yeast [33].
• Association of RhoA and CDC42 with RhoGDI was further suggested by coelution of these proteins with RhoGDI at an estimated size of approximately 45 kDa after gel-filtration chromatography [34].
• Gel overlay assays and affinity chromatography experiments showed that MIHCK interacted with GTPgammaS (guanosine 5'-3-O-(thiotriphosphate))-labeled Cdc42 and Rac1 but not RhoA [35].
• Using cell fractionation and immunolocalization techniques, we have investigated the subcellular localization of Cdc42p [36].

References