CDC42 (cell division cycle 42 (GTP binding protein, 25kDa))

2008-12-01   Fátima Valdés-Mora , Teresa Gómez del Pulgar , Juan Carlos Lacal 

Translational Oncology Unit CSIC-UAM- La Paz Centro Nacional de Biotecnologia C\\\/ Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain





This gene can be found on Chromosome 1 at location 22,235,157-22,292,024.


The DNA sequence contains 6 exons and the transcript length is 1,512 bps translated to a 191 residues protein. Alternative splicing of this gene results in three transcript variants that encode two isoforms. The transcript variants 1 and 3 encode the same isoform 1. The variant 3 has an additional exon in the 5 UTR compared to variant 1. The variant 2 encodes isoform 2 and differs from variant 1 at the 3 region including a small part of the coding region and the entire 3 UTR.



CDC42 encodes a 21.3 kDa, 191 amino acids small GTPase protein that belongs to the Rho family of Ras GTPases superfamily. There are two isoforms produced by alternative splicing from a single gene. The isoform 1, also known as placental isoform, Cdc42p, Cdc42Hs or Cdc42a (Shinjo et al., 1990) has the same amino acid length than isoform 2 but differs from the isoform 2 as follows: 163 R (isoform 2) --> K (isoform 1) and at the C terminus in ten amino acids: 182-191 TQPKRKCCIF (isoform 2) --> PKKSRRCVLL (isoform 1). The isoform 2, also known as brain isoform, Cdc42b or G25K (Munemitsu et al., 1990), has been chosen as the canonical sequence.
The contribution of CDC42 to cancer progression seems to be tissue specific due to it has been found to have pro-oncogenic and anti-oncogenic properties depending on cellular context.
CDC42 activity regulation:
CDC42 switches between an active GTP-bound state and inactive GDP-bound state. This cycle is regulated by its intrinsic GTPase activity and its interaction with three protein families: guanine exchange factors (GEFs), guanine dissociation inhibitors (GDIs) and GTPase activating proteins (GAPs) (Bishop and Hall, 2000). Due to the exchange of GDP to GTP by CDC42 itself occurs very slowly, GEFs promote such exchange from GDP- to GTP-bound state. GAPs increase the GTP hydrolysis activity. Furthermore, CDC42 is able to interact with membranes via post-translational C-terminal geranylgeranyl lipid modification, however it can be found as a soluble complex association with RhoGDI. Thus, RhoGDIs sequester CDC42-GDP in the cytoplasm through a transfer of geranylgeranyl moiety from membrane to GDI and inhibit its spontaneous GDP/GTP exchange activity. Additionally, CDC42 can be phosphorylated by diverse kinases which regulate its interaction with RhoGDIs (Forget et al., 2002; DerMardirossian and Bokoch, 2005). To date over 70 Rho-GEFs, 60 Rho-GAPs and 3 Rho-GDIs have been identified in mammals, reflecting the complexity of regulation of these classes of proteins.
Biochemical studies of CDC42 show that, in response to external signals originating from cell surface receptors and cell adhesion molecules, GEFs engage CDC42 and form macromolecular complexes with scaffolding proteins and/or kinases and with specific effector molecules triggering a signalling cascade to direct cellular responses (Cerione, 2004). CDC42 acts as a signal transduction convergence point in intracellular signalling networks, and mediates multiple signalling pathways, including tyrosine kinase receptors, heterodimeric G-protein coupled receptors (GPCR), cytokine receptors, integrins, and physical and chemical stress (Etienne-Manneville, 2004). The upstream signals include cytokines, growth factors, GPCR ligands, proteoglycans and integrins (Symons and Settleman, 2000).
CDC42 structure:
Rho proteins consist only of the GTPase domain and short N-terminal and C-terminal extensions. This family is defined by the presence of a Rho-type GTPases like domain located between the fifth β strand and the fourth α helix of their small GTPase domain (Valencia et al., 1991). A comparison of the RhoA-GDP and [Val14]RhoA-GTP[S] crystal structures, reveals that the conformational differences between the GTP and GDP-bound forms are restricted primarily to two surface loops, named switch regions I and II that correspond to CDC42 amino acids 26 and 59 (Bishop and Hall, 2000). Effector proteins utilize such differences to discriminate between the GTP- and GDP- bound forms, although they also interact with other regions of CDC42 protein. Nuclear magnetic resonance (NMR) structures of CDC42 bound to activated CDC42-associated tyrosine kinase (ACK) (amino acids 504-545) and WASP (amino acids 230-288) have provided a better understanding about Rho GTPase-effector interactions. ACK and WASP both contain the conserved GTPase-binding consensus site, the CRIB (CDC42/Rac-interactive binding) motif, which is present in many, though not all, Rac- and CDC42-binding proteins (Abdul-Manan et al., 1999; Mott et al., 1999). This motif is necessary, but not sufficient, for strong binding of the effector to CDC42.
CDC42 effectors:
To date, at least 23 proteins have been identified as potential effectors for CDC42 primarily using affinity chromatography and the yeast two-hybrid system. These proteins are: p70 S6 kinase; MLK2 and MLK3; MEKK1 and MEKK4; PAK1, PAK2, PAK3 and PAK4; MRCKα and MRCKβ; ACK1 and ACK2; PI3K; PLD; PLC-β2; WASP and N-WASP; MSE55 and BORGs; IQGAP1 and IQGAP2; and CIP-4 (Bishop and Hall, 2000).
The most common mechanism of effector activation by Rho GTPases appears to be the disruption of intramolecular autoinhibitory interactions, to expose functional domains within the effector protein.
CDC42 itself seems to be unable to discriminate downstream effectors because most of them, such as PAK, WASP, ACK and MLK3, have the same CDC42-interaction motif with similar binding affinity to active CDC42. So the specificity of CDC42 signalling seems to be dependent on: upstream signals that activate CDC42-GEFs; the interaction of these RhoGEFs with CDC42 effectors forming macromolecular complexes; the translocation of CDC42-effectors by RhoGEFs and RhoGDIs; and CDC42 signalling network components (Sinha and Yang, 2008).


CDC42 isoform 1 is the most commonly studied form and it is expressed ubiquitously, whereas the isoform 2 is restricted to the brain (Wennerberg and Der, 2004).


In mammalian cells CDC42 is predominantly localized at Golgi apparatus but it has been also localized at the plasma membrane and on numerous vesicular structures dispersed throughout the cytosol (Erickson et al., 1996; Osmani et al., 2006).


CDC42 is one of the best characterized members of Rho family. Their involvements in regulating actin cytoskeleton and cell polarity are the best studied functions. In this context, CDC42 plays a role in a wide variety of cellular processes that are dependent on the actin cytoskeleton, such as cytokinesis, phagocytosis, cell migration, morphogenesis, chemotaxis and axon guidance.
Physiologically, CDC42 is implicated in other essential cellular processes such as axon myelination, intracellular trafficking, gene transcription, cell-cycle regulation and cell fate determination. However, the contribution of CDC42 in these different cellular processes could be cell-type specific (Wang and Zheng, 2007; Heasman and Ridley, 2008).
Deregulation of CDC42 is found in several pathogenic processes such as cancer, neurodegenerative disorders and cardiovascular disease (Boettner and Van Aelst, 2002; Broman et al., 2007).
Role in actin cytoskeleton organization: regulation of filopodium formation:
CDC42 regulates signal transduction pathways linking various membrane receptors to the finally filopodia formation in many cell types. Filopodia are thin protrusions that contain parallel bundles of actin filaments that extend from the leading edge in many migratory cells being able to function as sensory probes or in the establishment of cell-cell contacts, for example in axon guidance and neurite extension (Gupton and Gertler, 2007).
CDC42 induces actin polymerization to the filopodia formation by binding to Wiskott-Aldrich syndrome protein (WASP) or through the insulin-receptor substrate p53 (IRSp53) Tyr kinase to induce branched actin filaments using the actin-related protein-2/3 (ARP2/3) complex. CDC42 also induces actin polymerization by activation of mammalian diaphanous2 (mDia2). Moreover, CDC42-mediated activation of the Ser/Thr kinase PAK (p21-activated kinase) phosphorylates LIM kinase (LIMK), which phosphorylates and inhibits cofilin, thereby regulating actin filament turnover. In the neural growth cone, CDC42 might result in reduced cofilin phosphorylation by unknown mechanism, thereby stimulating actin polymerization and filopodium formation (Heasman and Ridley, 2008).
Role in axon myelination:
The formation of myelin sheaths in the central nervous system is the result of a complex series of events involving oligodendrocyte progenitor cell (OPC) proliferation, directed migration, and the morphological changes associated with axon ensheathment and myelination. Ablation of CDC42 in cells of the oligodendrocyte lineage leads to the formation of a unique and stage-specific myelination phenotype. This is characterized by the extraordinary enlargement of the inner tongue of the oligodendrocyte process and concomitant formation of a myelin outfolding as a result of abnormal accumulation of cytoplasm in this region (Thurnherr et al., 2006). Furthermore, OPCs, oligodendrocytes, and Schwann cells use actin polymerization-driven protrusion dependent on CDC42 effector N-WASP to advance in the processes for motility in the developing nervous system. In addition, it has been also demonstrated that p34 (a component of the Arp2/3 complex), WASP/WAVE proteins, actin, alpha-tubulin, Rac, CDC42, vinculin, and focal adhesion kinase are detected in water-shocked myelin purified from brain, so the same mechanism could be implicated in ensheathing axons at myelination (Bacon et al., 2007).
Role in migration and chemotaxis:
CDC42 has been involved in chemotaxis and directed migration of several cell types both in vitro and in vivo, including macrophages, T cells, fibroblasts and D melanogaster haemocytes (Heasman and Ridley, 2008). In macrophages, inhibition of CDC42 blocks chemotaxis toward CSF gradient without affecting mobility. Furthermore, CDC42 deletion in primary mouse embryonic fibroblasts (MEFs) causes abnormal cell spreading, reduced adhesion to fibronectin, defective mobility in wound healing, and decreases chemotaxis toward a serum gradient. These effects are associated with deficiencies of PAK1, GSK3β, myosin light chain and FAK phosporylation (Yang et al., 2006). In addition, an increase in CDC42 activity can stimulate migration speed, for example in neutrophils isolated from Cdc42GAP-knockout mice (Szczur et al., 2006). Conversely, directed migration of CDC42-null fibroblastoid cells has been reported to be normal (Wang and Zheng, 2007).
Role in cell polarity:
Polarity is involved in essentially every aspect of cell and developmental biology. All cell types polarize, at least transiently, during division or to generate specialized shapes and functions in proliferation, differentiation and morphogenesis. Moreover although the functional characteristics of cell polarity are extremely variable, depending on the cell type and the biological context, CDC42 has stood out as playing a central role in controlling of multiple signal transduction pathways which drives to cell polarity in all cell eukaryotic cells, irrespective of the biological context (Etienne-Manneville, 2004).
CDC42 seems to function primarily through the polarity protein partitioning-defective-6 (PAR6) and thereby with PAR3 and/or atypical protein kinase C (aPKC) isoforms to induce polarity in several cellular contexts (Goldstein and Macara, 2007). However, CDC42 can also function independently of the PAR complex through its effector myotonic-dystrophy-kinase-related CDC42-binding kinase (MRCK) (Gomes et al., 2005).
Role in cell cycle regulation and survival:
CDC42 is important in cell cycle through its involvement in G1/S-phase transition and its role in mitosis (Jaffe and Hall, 2005; Olson et al., 1995).
CDC42 blocks G1 progression in a variety of mammalian cell types, but the mechanisms are cell-type dependent and have proven difficult to elucidate. Multiple pathways seem to link CDC42 to the control of cyclin-D1 levels. The transcription of cyclin D1 is controlled by the ETS, AP-1 and nuclear factor-kappaB (NFkappaB), and many studies have been identified pathways that link CDC42 to these transcription factors (Perona et al., 1997; Sahai and Marshall, 2002). Furthermore, CDC42 stimulated the expression of cyclin E through its effector p70 S6 kinase (Chou et al., 2003).
During mitosis, spindle microtubules interact with chromosomes at the kinetochore, a complex of at least 50 proteins that includes the CDC42-specific effector mDia3. Inhibition of CDC42 or depletion of mDia3 causes a mitotic arrest in which many chromosomes are not properly attached to microtubules (Yasuda et al., 2004).
Furthermore, MEFS produced by gene targeting as CDC42 loss cell model are defective in G1/S-phase transition and survival, correlating with deficient NFkappaB transcription and defective JNK, p70 S6 kinase and ERK 1/2 activation (Yang et al., 2006). Moreover, in Cdc42GAP-/- hematopoietic stem/progenitor cells, the decrease in number of cells is associated with increased apoptosis of these cells and the activation of JNK-mediated apoptotic machinery (Wang et al., 2006).
Role in cell fate determination:
CDC42 is essential for skin progenitor cell differentiation into the hair follicle lineage by regulating beta-catenin turnover through CDC42-Par6-Par3-PKC ς-glycogen synthase kinase 3β signalling pathway (Wu et al., 2006). Moreover, CDC42 is important in the neural cell fate determination through the regulation of polarity following cell division at the apical surface mediated by the Par6-Par3-aPKC complex (Capello, 2006). Finally, conditional knock out of CDC42 in the bone marrow causes defects in multiple hematopoietic lineages, suppressing erythropoiesis but increasing myelopoiesis (Yang et al., 2007).
Role in intracellular trafficking:
In mammals, CDC42 is localized predominantly at Golgi complex. In Golgi apparatus, the activated form of CDC42 is able to associate with COPI complex. This complex is important in vesicle trafficking because regulates the intracellular trafficking and processing of EGF receptor. Several studies have demonstrated that CDC42 regulates polarized (basolateral) transport in Madin-Darby canine kidney (MDCK) cells. In addition, disruption of CDC42 function also inhibited both the basolateral transport of the low-density lipoprotein receptor and retrograde transport from the Golgi to the ER. Despite these clues, the underlying mechanistic role of CDC42 in trafficking remains unknown (Cerione, 2004).
Furthermore, secramine, a molecule that inhibits membrane traffic out of the Golgi apparatus, inhibits activation of CDC42, mimicking the effects of dominant-negative CDC42 expression on protein export from the Golgi and on Golgi polarization in migrating cells (Pelish et al., 2006).
Role in transcriptional control:
The activation of many Rho effector proteins results in the modulation of the activity of several transcription factors that play an important role at various levels of Rho signalling implicating them in many cellular functions (Benitah et al., 2004). Specifically, CDC42 is implicated in the regulation of several transcription factors such as NFkappaB, STAT3 and SRF. CDC42 is able to activate the NFkappaB pathway through JNK signalling dependent pathway by a mechanism that involves phosphorylation of IκBα and translocation of p50/p50 and p50/p65 dimers to the nucleus (Perona et al., 1997). In addition, the silencing of CDC42 in two bladder cancer cell lines decrease phosphorylation levels of the transcription factor STAT3 leading to the inhibition of the cellular proliferation and the induction of apoptosis (Wu et al., 2008). The constitutively active form of CDC42, Cdc42.V12, induces transcription via SRF through JNK/SAPK activation and acts synergistically at the c-fos serum response element (SRE) with signals that activate TCF (ternary complex factor) (Hill et al., 1995).
Recently, it has been described a novel mechanism of transcriptional regulation mediated by CDC42 through the promoter hypermethylation of the ID4 gene in a colorectal cancer cell line (Gomez del Pulgar et al., 2008).
Dual role in cancer:
It has been suggested that the contribution of CDC42 in tumour progression is tissue-specific. Depending on the cellular context, this Rho GTPase promotes or inhibits tumour progression. However, there are more cell types where CDC42 is a pro-oncogenic factor (Vega and Ridley, 2008).
CDC42 contributes to cancer development through its different roles in: intracellular trafficking, cell cycle regulation and survival, polarity, migration and transcriptional control (Vega and Ridley, 2008).
1. Intracellular trafficking: This process has been associated with the control of cell growth by the regulation of the processing and degradation of EGF receptor. The overexpression of a mutant form of CDC42 (F28L), which dissociates from GDP at a rate that is at least 50-fold faster than wild-type CDC42, produces an accumulation of EGF receptors. This accumulation causes an excessive mitogenic signalling through the Ras-Erk pathway that leads to cellular transformation (Wu et al., 2003). In this context, CDC42 stimulates and contributes to Ras-induced transformation in mouse fibroblasts in vitro (Qiu et al., 1997).
2. Cell cycle regulation and apoptosis: Many of the effects of Rho GTPases on G1 progression are thought to reflect the crucial role of anchorage- or adhesion-dependent signals for cell proliferation (Jaffe and Hall, 2005). Indeed, CDC42 could affect cell cycle progression by regulating chromosome misalignment during cell division, leading to multinucleated cells (Yasuda et al., 2006). Moreover, CDC42 contributes to immune escape of cancer as mediator of resistance to cytotoxic T lymphocytes (CTL)-mediated growth suppression of MEFs and HCT116 colorectal cancer cells. This event occurs through the prevention of CTL -induced apoptosis via mitogen-activated protein kinase (MAPK) signalling and posttranscriptional stabilization of Bcl-2 (Marques et al., 2008). By contrast, the overexpression of the active form of CDC42 in Jurkat T lymphocytes induces apoptosis through a JNK-dependent signaling pathway leading to caspase activation (Chuang et al., 1997).
3. Polarity and migration: CDC42 is predicted to inhibit invasion by promoting epithelial polarity, yet conversely also stimulated migration. Indeed, CDC42 contributes to cancer cell invasion in single cells with a mesenchymal morphology in vitro. It is also important for collective cancer cell invasion, where it acts through its effector MRCK to stimulate actomyosin contractility (Friedl and Wolf, 2003). In addition Rho activity alteration (RhoA, Rac1 and CDC42) has been linked with loss of polarity, an important fate in epithelial-mesenchymal transition (EMT) (Patel et al., 2005).
4. Transcriptional control: The implication of CDC42 in gene transcription has been also proposed as a mechanism of participation in tumour progression (Benitah et al., 2004). In this context, the activation of NFkappaB pathway by RhoA, Rac1 and CDC42 leads to the transcriptional expression of COX2, a protein highly implicated in cancer and inflammation processes (Benitah et al., 2003). Furthermore, RNAi-mediated inhibition of CDC42 produces a significant inhibition of cell proliferation and an induction of apoptosis in human in bladder cancer cell lines through the downregulation of STAT3 phosphorylated levels (Wu et al., 2008). Recently, the epigenetic transcriptional silencing of the putative tumour suppressor gene ID4 by CDC42 seems to be an important event in colorectal carcinogenesis (Gomez del Pulgar et al., 2008).
Finally, the involvement of CDC42 in the carcinogenic process is highly associated to aberrant expression and activity of the protein (Gomez del Pulgar et al., 2005; 2008).



Unlike Ras proteins that are constitutively activated to oncoproteins by point mutations in human cancer, Rho family proteins are likely to be activated in vivo by different mechanisms such as overexpression of the GTPase or deregulation of the expression of regulatory proteins. Thus, no point mutations in the coding sequence of CDC42 gene were found in invasive breast and colon cancer samples (Rihet et al., 2001).

Implicated in

Entity name
Breast cancer
CDC42 protein levels are highly increased in breast cancer compared with the corresponding normal tissue from the same patient (Fritz et al., 1999; 2002). This evidence is enforced with the results from a mouse model of breast carcinoma, where the expression of a dominant inhibitory mutant of CDC42 reduces the number of focal contacts, inhibits colony formation in soft agar in vitro and affects cell growth in vivo. Furthermore, this inactive form reduced intravasation into the peripheral blood and lung metastases (Bouzahzah et al., 2001).
ErbB1 and ErbB2 are often overexpressed in breast cancer and such overexpression is correlated with poor prognosis. Activated CDC42 contributes to the accumulation of ErbB1 in cells through the regulation of c-Cbl function. Thus, different therapeutic strategies targeting ErbB receptors and CDC42 have been proposed in this cancer type (Hirsch and Wu, 2007).
Entity name
Testicular cancer
Western blot analyses revealed that CDC42 was significantly overexpressed in tumoral samples from 57 patients with testicular germ cell tumors compared with each non-tumor counterparts. The expression of CDC42 protein was significantly greater in tumors of higher stages than lower stages. Thus, CDC42 may be involved in the progression of testicular germ cell tumors (Kamai et al., 2004).
Entity name
Head and neck squamous cell carcinoma
Immunohistochemical analysis has revealed that the protein CDC42 is overexpressed in head and neck cancer specimens (n=15). Moreover, CDC42 overexpression is found in premalignant and squamous cell cancer cell lines relative to normal keratinocytes (Abraham, 2001).
Entity name
CDC42 protein expression is increased in tumoral samples from patients with fatal outcome using immunohistochemical assays. In this group a positive correlation is found between melanocytic CDC42 expression and Breslow thickness (Tucci et al., 2007). Besides, activation of CDC42 by surface antigens has been implicated in melanoma cell growth and invasion signals to promote cell-spreading. In keeping with this, autotoxin promotes invasiveness and angiogenesis through CDC42 in this cancer type (Eisenmann et al., 1999; Jung et al., 2002). In addition, DOCK10, a CDC42 GEF, activates CDC42 promoting amoeboid invasion of melanoma cells (Gadea et al., 2008).
Entity name
Colorectal cancer
The protein levels of CDC42 are found to be overexpressed with high incidence (60%) in colorectal cancer samples. Such overexpression is significantly correlated with the histopathological grade of the tumor reflecting the plausible role of CDC42 in cell polarity and actin cytoskeleton. In addition, the CDC42 overexpression is associated with silencing of the putative tumor suppressor gene ID4 with statistical significance (Gomez del Pulgar et al., 2008). Moreover, leptin induces CDC42 activation promoting lamellopodium formation and concomitantly enhanced cell invasion in human colon cancer cells (Jaffe and Schwartz, 2008).
Entity name
Hepatocellular carcinoma
Western blot expression of CDC42 in twenty patients with hepatocellular carcinoma (HCC) is higher in cancer tissues with HBV infection than para-cancerous liver tissues and cancer tissues without HBV infection (Chang et al., 2007). In addition, EB1 overexpression was associated with poorly differentiated HCC, which generally correlate with poor prognosis of these patients. Network analysis reveals that EB1 functions downstream of RhoA and CDC42 by interacting with mDia2 (Orimo et al., 2008). In the other hand, in a human HCC cell line, the protein BNIPL-2 is involved in the activation of CDC42 and enhances the migration and invasion of cancer cells in vitro, but also promotes cancer metastasis in vivo (Xie et al., 2007). By contrast, liver conditional CDC42 knock out mice suffer a chronic liver disease that leads to hepatocarcinogenesis. These tumors grow slowly and lack expression of nuclear beta-catenin. Lung metastases are observed at the late stage of carcinogenesis (Van Hengel et al., 2008).
Entity name
Lung cancer
Although alterations of CDC42 expression or activation have not been described in any human lung tumor tissue yet, its inactivation or downregulation might be involved in lung tumor progression. Indeed, mRNA levels of CDC42 showed no change in adenomas, but were underexpressed in adenocarcinomas in mouse lung cancer considering as candidate "lung tumor progression" gene because its expression changes may specifically affect lung tumor progression in mice (Yao et al., 2002). In addition, in non small cell lung cancer (NSCLC) cell lines the tumor suppressor gene LKB1 maintains active CDC42 levels and downstream PAK phosphorylation to the regulation of epithelial cell polarity (Zang, 2008).
Entity name
Other cancer types
Although to date there is no data available about the alteration of CDC42 expression or activation in patients with bladder cancer or lymphoma, there are some evidences that point CDC42 as an important factor in the development and progression of these cancer types. In the case of lymphomas, in anaplastic large cell lymphoma (ALCL) cell line, the oncogenic fusion protein NPM-ALK forms a complex with the GEF VAV1, enhancing its activation and consequently increasing CDC42 activation. This signalling regulates cell shape and migration. Genetic knockdown of CDC42 or pharmacological inhibition of CDC42 by secramine resulted in a cell cycle arrest and apoptosis of ALCL cells. Furthermore, CDC42 is necessary for the growth and the maintenance of already established lymphomas in vivo (Ambrogio et al., 2008).
In the case of bladder cancer, CDC42 silencing results in a significant inhibition of cell proliferation from G0/G1- to S-phase in two human bladder-cancer cell lines, EJ and T24, and an induction of apoptosis of EJ cells. These results suggest that CDC42 silencing may be a novel approach for therapy of bladder cancer (Wu et al., 2008).


Pubmed IDLast YearTitleAuthors
103605781999Structure of Cdc42 in complex with the GTPase-binding domain of the 'Wiskott-Aldrich syndrome' protein.Abdul-Manan N et al
115685562001Motility-related proteins as markers for head and neck squamous cell cancer.Abraham MT et al
189741342008The anaplastic lymphoma kinase controls cell shape and growth of anaplastic large cell lymphoma through Cdc42 activation.Ambrogio C et al
174051462007N-WASP regulates extension of filopodia and processes by oligodendrocyte progenitors, oligodendrocytes, and Schwann cells-implications for axon ensheathment at myelination.Bacon C et al
155887662004Rho GTPases in human cancer: an unresolved link to upstream and downstream transcriptional regulation.Benitah SA et al
108164162000Rho GTPases and their effector proteins.Bishop AL et al
119434722002The role of Rho GTPases in disease development.Boettner B et al
118448702001Rho family GTPases regulate mammary epithelium cell growth and metastasis through distinguishable pathways.Bouzahzah B et al
175741222007Cdc42 regulates the restoration of endothelial adherens junctions and permeability.Broman MT et al
168920582006The Rho-GTPase cdc42 regulates neural progenitor fate at the apical surface.Cappello S et al
150036212004Cdc42: new roads to travel.Cerione RA et al
182511602007Different expression of apoptotic proteins between HBV-infected and non-HBV-infected hepatocellular carcinoma.Chang CS et al
128428762003Cdc42 promotes G1 progression through p70 S6 kinase-mediated induction of cyclin E expression.Chou MM et al
93079661997The small GTPase Cdc42 initiates an apoptotic signaling pathway in Jurkat T lymphocytes.Chuang TH et al
159219092005GDIs: central regulatory molecules in Rho GTPase activation.DerMardirossian C et al
105876471999Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130cas.Eisenmann KM et al
89001671996Mammalian Cdc42 is a brefeldin A-sensitive component of the Golgi apparatus.Erickson JW et al
150206692004Cdc42--the centre of polarity.Etienne-Manneville S et al
117723962002Phosphorylation states of Cdc42 and RhoA regulate their interactions with Rho GDP dissociation inhibitor and their extraction from biological membranes.Forget MA et al
127247342003Tumour-cell invasion and migration: diversity and escape mechanisms.Friedl P et al
122377742002Rho GTPases in human breast tumours: expression and mutation analyses and correlation with clinical parameters.Fritz G et al
103282161999Rho GTPases are over-expressed in human tumors.Fritz G et al
188351692008DOCK10-mediated Cdc42 activation is necessary for amoeboid invasion of melanoma cells.Gadea G et al
179811312007The PAR proteins: fundamental players in animal cell polarization.Goldstein B et al
158826262005Nuclear movement regulated by Cdc42, MRCK, myosin, and actin flow establishes MTOC polarization in migrating cells.Gomes ER et al
185757652008Cdc42 is highly expressed in colorectal adenocarcinoma and downregulates ID4 through an epigenetic mechanism.Gómez Del Pulgar T et al
158921192005Rho GTPase expression in tumourigenesis: evidence for a significant link.Gómez del Pulgar T et al
177121392007Filopodia: the fingers that do the walking.Gupton SL et al
187197082008Mammalian Rho GTPases: new insights into their functions from in vivo studies.Heasman SJ et al
76005831995The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF.Hill CS et al
172885262007Cdc42: an effector and regulator of ErbB1 as a strategic target in breast cancer therapy.Hirsch DS et al
162124952005Rho GTPases: biochemistry and biology.Jaffe AB et al
187670362008Leptin promotes motility and invasiveness in human colon cancer cells by activating multiple signal-transduction pathways.Jaffe T et al
124825912002Cdc42 and Rac1 are necessary for autotaxin-induced tumor cell motility in A2058 melanoma cells.Jung ID et al
152691552004Overexpression of RhoA, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer.Kamai T et al
179714882008An immune escape screen reveals Cdc42 as regulator of cancer susceptibility to lymphocyte-mediated tumor suppression.Marques CA et al
103605791999Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK.Mott HR et al
21222361990Molecular cloning and expression of a G25K cDNA, the human homolog of the yeast cell cycle gene CDC42.Munemitsu S et al
76525751995An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1.Olson MF et al
189372832008Proteomic profiling reveals the prognostic value of adenomatous polyposis coli-end-binding protein 1 in hepatocellular carcinoma.Orimo T et al
170817552006Scrib controls Cdc42 localization and activity to promote cell polarization during astrocyte migration.Osmani N et al
159017672005RhoGTPase activation is a key step in renal epithelial mesenchymal transdifferentiation.Patel S et al
164080912006Secramine inhibits Cdc42-dependent functions in cells and Cdc42 activation in vitro.Pelish HE et al
90428601997Activation of the nuclear factor-kappaB by Rho, CDC42, and Rac-1 proteins.Perona R et al
91548441997Cdc42 regulates anchorage-independent growth and is necessary for Ras transformation.Qiu RG et al
117686132001Mutation status of genes encoding RhoA, Rac1, and Cdc42 GTPases in a panel of invasive human colorectal and breast tumors.Rihet S et al
126351762002RHO-GTPases and cancer.Sahai E et al
21247041990Molecular 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.Shinjo K et al
185584782008Cellular signaling for activation of Rho GTPase Cdc42.Sinha S et al
109985972000Rho family GTPases: more than simple switches.Symons M et al
169316272006Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils.Szczur K et al
170211672006Cdc42 and Rac1 signaling are both required for and act synergistically in the correct formation of myelin sheaths in the CNS.Thurnherr T et al
179708062007Involvement of E-cadherin, beta-catenin, Cdc42 and CXCR4 in the progression and prognosis of cutaneous melanoma.Tucci MG et al
20295111991The ras protein family: evolutionary tree and role of conserved amino acids.Valencia A et al
184603422008Rho GTPases in cancer cell biology.Vega FM et al
161747572006Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment.Wang L et al
171619472007Cell type-specific functions of Rho GTPases revealed by gene targeting in mice.Wang L et al
150206702004Rho-family GTPases: it's not only Rac and Rho (and I like it).Wennerberg K et al
177058012008RNA-interference-mediated Cdc42 silencing down-regulates phosphorylation of STAT3 and suppresses growth in human bladder-cancer cells.Wu F et al
145055712003Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation.Wu WJ et al
165108732006Cdc42 controls progenitor cell differentiation and beta-catenin turnover in skin.Wu X et al
172737402007BNIPL-2 promotes the invasion and metastasis of human hepatocellular carcinoma cells.Xie L et al
177028962007Cdc42 critically regulates the balance between myelopoiesis and erythropoiesis.Yang L et al
121730532002Differentially expressed genes associated with mouse lung tumor progression.Yao R et al
150851372004Cdc42 and mDia3 regulate microtubule attachment to kinetochores.Yasuda S et al
167163042006An essential role of Cdc42-like GTPases in mitosis of HeLa cells.Yasuda S et al
182454742008The tumor suppressor LKB1 regulates lung cancer cell polarity by mediating cdc42 recruitment and activity.Zhang S et al
183253912008Continuous cell injury promotes hepatic tumorigenesis in cdc42-deficient mouse liver.van Hengel J et al

Other Information

Locus ID:

NCBI: 998
MIM: 116952
HGNC: 1736
Ensembl: ENSG00000070831


dbSNP: 998
ClinVar: 998
TCGA: ENSG00000070831


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Axon guidanceKEGGko04360
VEGF signaling pathwayKEGGko04370
Focal adhesionKEGGko04510
Adherens junctionKEGGko04520
Tight junctionKEGGko04530
T cell receptor signaling pathwayKEGGko04660
Leukocyte transendothelial migrationKEGGko04670
Regulation of actin cytoskeletonKEGGko04810
GnRH signaling pathwayKEGGko04912
Epithelial cell signaling in Helicobacter pylori infectionKEGGko05120
Pathogenic Escherichia coli infectionKEGGko05130
Renal cell carcinomaKEGGko05211
Pancreatic cancerKEGGko05212
MAPK signaling pathwayKEGGhsa04010
Axon guidanceKEGGhsa04360
VEGF signaling pathwayKEGGhsa04370
Focal adhesionKEGGhsa04510
Adherens junctionKEGGhsa04520
Tight junctionKEGGhsa04530
T cell receptor signaling pathwayKEGGhsa04660
Leukocyte transendothelial migrationKEGGhsa04670
Regulation of actin cytoskeletonKEGGhsa04810
GnRH signaling pathwayKEGGhsa04912
Epithelial cell signaling in Helicobacter pylori infectionKEGGhsa05120
Pathogenic Escherichia coli infectionKEGGhsa05130
Pathways in cancerKEGGhsa05200
Renal cell carcinomaKEGGhsa05211
Pancreatic cancerKEGGhsa05212
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Bacterial invasion of epithelial cellsKEGGko05100
Bacterial invasion of epithelial cellsKEGGhsa05100
Salmonella infectionKEGGko05132
Salmonella infectionKEGGhsa05132
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Costimulation by the CD28 familyREACTOMER-HSA-388841
CD28 co-stimulationREACTOMER-HSA-389356
CD28 dependent Vav1 pathwayREACTOMER-HSA-389359
Innate Immune SystemREACTOMER-HSA-168249
Fcgamma receptor (FCGR) dependent phagocytosisREACTOMER-HSA-2029480
Regulation of actin dynamics for phagocytic cup formationREACTOMER-HSA-2029482
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
GPVI-mediated activation cascadeREACTOMER-HSA-114604
Factors involved in megakaryocyte development and platelet productionREACTOMER-HSA-983231
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
EGFR downregulationREACTOMER-HSA-182971
Signaling by VEGFREACTOMER-HSA-194138
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK6/MAPK4 signalingREACTOMER-HSA-5687128
Signaling by Rho GTPasesREACTOMER-HSA-194315
Rho GTPase cycleREACTOMER-HSA-194840
RHO GTPase EffectorsREACTOMER-HSA-195258
RHO GTPases activate PAKsREACTOMER-HSA-5627123
RHO GTPases activate KTN1REACTOMER-HSA-5625970
RHO GTPases activate IQGAPsREACTOMER-HSA-5626467
RHO GTPases Activate WASPs and WAVEsREACTOMER-HSA-5663213
RHO GTPases Activate ForminsREACTOMER-HSA-5663220
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (12/13) signalling eventsREACTOMER-HSA-416482
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Semaphorin interactionsREACTOMER-HSA-373755
Sema4D in semaphorin signalingREACTOMER-HSA-400685
Sema4D induced cell migration and growth-cone collapseREACTOMER-HSA-416572
Netrin-1 signalingREACTOMER-HSA-373752
DCC mediated attractive signalingREACTOMER-HSA-418885
Signaling by Robo receptorREACTOMER-HSA-376176
Inactivation of Cdc42 and RacREACTOMER-HSA-428543
EPH-Ephrin signalingREACTOMER-HSA-2682334
EPHB-mediated forward signalingREACTOMER-HSA-3928662
CDO in myogenesisREACTOMER-HSA-375170
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
128879222003Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils.275
157935692005Regulation of PTEN by Rho small GTPases.193
190011282008Cdc42 controls spindle orientation to position the apical surface during epithelial morphogenesis.179
157230502005Cdc42-MRCK and Rho-ROCK signalling cooperate in myosin phosphorylation and cell invasion.147
153616242004Activation of endogenous Cdc42 visualized in living cells.146
128879232003Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42.143
190391032009AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling.136
185417052008The interaction of IQGAP1 with the exocyst complex is required for tumor cell invasion downstream of Cdc42 and RhoA.133
119072712002Transforming growth factor-beta-induced mobilization of actin cytoskeleton requires signaling by small GTPases Cdc42 and RhoA.123
170748832006Differential activation and function of Rho GTPases during Salmonella-host cell interactions.107


Fátima Valdés-Mora ; Teresa Gómez del Pulgar ; Juan Carlos Lacal

CDC42 (cell division cycle 42 (GTP binding protein, 25kDa))

Atlas Genet Cytogenet Oncol Haematol. 2008-12-01

Online version: