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Gene Review

CDC42  -  cell division cycle 42

Homo sapiens

Synonyms: CDC42Hs, Cell division control protein 42 homolog, G25K, G25K GTP-binding protein
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Disease relevance of CDC42

  • Surprisingly, pertussis toxin and overexpression of the free Gbetagamma-specific sequestering minigene hbetaARK1(495) also inhibit EGLT-mediated CDC42 and Rac1 activation completely [1].
  • CDC42 and Rac1 are implicated in the activation of the Nef-associated kinase and replication of HIV-1 [2].
  • Ad internalization was significantly reduced in cells treated with Clostridium difficile toxin B and in cells expressing a dominant-negative Rac or CDC42 but not a H-Ras protein [3].
  • PAK1, a Rac/CDC42-dependent Ser/Thr kinase, is required for both neurofibromatosis (NF) and RAS transformation in vivo [4].
  • Here, we show that Cdc42 is required for the actin-based motility of Shigella [5].

Psychiatry related information on CDC42

  • The biological mechanisms underlying the mental retardation associated with mutation of the ARHGEF6 gene, a Rac1/Cdc42 exchange factor, are still unknown, although defects in the plasticity of synaptic networks have been postulated [6].
  • Individual differences in the in vitro response to cyclosporin A (CsA): possible heterogeneity in the involvement of the CD28-B7/BB1 pathway [7].

High impact information on CDC42

  • The p21-activated kinases (PAKs) 1-3 are serine/threonine protein kinases whose activity is stimulated by the binding of active Rac and Cdc42 GTPases [8].
  • Using a three-dimensional model of epithelial morphogenesis, report that the phosphatase PTEN and phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P(2)] regulate the GTPase Cdc42 and the kinase aPKC to generate the apical plasma membrane domain and maintain apical-basolateral polarity [9].
  • PTEN-Mediated Apical Segregation of Phosphoinositides Controls Epithelial Morphogenesis through Cdc42 [10].
  • Using functional and proteomic screens of proteins that regulate the Cdc42 GTPase, we have identified a network of protein interactions that center around the Cdc42 RhoGAP Rich1 and organize apical polarity in MDCK epithelial cells [11].
  • In this issue of Cell, provide intriguing evidence for a new pathway that links polarity proteins and vesicle transport to the maintenance of tight junctions, through the control of Cdc42 by Rich1, a GTPase-activating protein [12].

Chemical compound and disease context of CDC42

  • Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130cas [13].
  • These approximately 190-kDa myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs) preferentially phosphorylate nonmuscle myosin light chain at serine 19, which is known to be crucial for activating actin-myosin contractility [14].
  • We also show that the signaling pathways leading to Rac and Cdc42 activation in HL-60 cells involve G proteins sensitive to pertussis toxin, as well as tyrosine kinase and phosphatidylinositol 3-kinase activities [15].
  • Reduced AM mannose receptor-mediated Cdc42 and Rho activation in the context of HIV infection may represent a mechanism that contributes to the pathogenesis of opportunistic pneumonia [16].
  • Inhibition of Cdc42 and Rac1 with Clostridium difficile toxin B inhibited apoA-I-induced cholesterol efflux, whereas inhibition of Rho with Clostridium botulinum C3-exoenzyme exerted opposite effects [17].

Biological context of CDC42

  • Thus, the glucose- and GTP-dependent carboxyl methylation of G-proteins such as CDC42 is an obligate step in the stimulus-secretion coupling of nutrient-induced insulin secretion, but not in the exocytotic event itself [18].
  • Fibronectin matrix regulates activation of RHO and CDC42 GTPases and cell cycle progression [19].
  • The commonly studied members (Rho, Rac, and CDC42) regulate actin reorganization, affecting diverse cellular responses, including adhesion, cytokinesis, and motility [20].
  • CDC42, a member of the Rho family of small GTP-binding proteins, regulates cytoskeletal rearrangements required for cell division [21].
  • Activating mutations in CDC42 that are refractory to GTPase activation confer a phenotype of large, multinucleated cells [21].

Anatomical context of CDC42

  • Confocal microscopic data indicated that CDC42 is localized only in islet endocrine cells but not in acinar cells of the pancreas [18].
  • Glucose- and GTP-dependent stimulation of the carboxyl methylation of CDC42 in rodent and human pancreatic islets and pure beta cells. Evidence for an essential role of GTP-binding proteins in nutrient-induced insulin secretion [18].
  • AFC (a specific inhibitor of prenyl-cysteine carboxyl methyl transferases) blocked the carboxyl methylation of CDC42 in five types of insulin-secreting cells, without blocking GTPgammaS-induced translocation, implying that methylation is a consequence (not a cause) of transfer to membrane sites [18].
  • Spreading of differentiating human monocytes is associated with a major increase in membrane-bound CDC42 [22].
  • Here, using mice deficient in the CDC42 regulator CDC42 GTPase-activating protein (CDC42GAP), we demonstrate that CDC42 activity separately regulates neutrophil motility and directionality [23].

Associations of CDC42 with chemical compounds

  • CDC42 undergoes a guanine nucleotide-specific membrane association and carboxyl methylation in normal rat islets, human islets, and pure beta (HIT or INS-1) cells [18].
  • Like other small GTP-binding proteins, CDC42 is activated by a guanosine exchange factor and inactivated by a GTPase-activating protein (GAP) [21].
  • A glutathione S-transferase fusion protein containing the three boxes derived from the new clone strongly stimulated the GTPase activity of CDC42 but was much less effective on other Rho proteins [21].
  • We conclude that WASp represents a connection between protein tyrosine kinase signaling pathways and CDC42 function in cytoskeleton and cell growth regulation in hematopoietic cells [24].
  • P21-activated kinases (PAKs) are a family of serine/threonine kinases whose diverse cellular functions in cytoskeletal reorganisation, cell motility, transformation and cell death are regulated both by the binding of the small RhoGTPases RAC and CDC42 and by RhoGTPase independent mechanisms [25].
  • The binding of an effector protein induced significant changes in the Trp-32 emission specifically from GMP-PCP-bound Cdc42, as well as in the phosphate resonances for GTP bound to this G-protein as indicated in NMR studies [26].

Physical interactions of CDC42

  • TC10 exhibits sequence similarity to Cdc42 and has been reported to bind N-WASP [27].
  • Thus we propose a model in which GTP-bound Cdc42/Rac binds MLK3 and disrupts SH3-mediated autoinhibition leading to dimerization and activation loop autophosphorylation [28].
  • Deletion of the Cdc42-binding domain of CIP4 did not affect the colocalization of WASP with microtubules in vivo [29].
  • Site-directed mutagenesis confirmed that an R235K or R238K mutation severely impaired the BNIP-2 GAP activity without affecting its binding to Cdc42 [30].
  • Therefore the Rac1/CDC42-coupled pathway(s) is a candidate that transduces and facilitates cross-talk between the CD28 costimulatory signal and the TCR signal [31].

Enzymatic interactions of CDC42

  • Despite having the ability to recognize this chimeric Cdc42, P-Rex2 is unable to catalyze nucleotide exchange on Cdc42, suggesting that recognition of substrate and catalysis are two distinct events [32].

Co-localisations of CDC42


Regulatory relationships of CDC42


Other interactions of CDC42

  • Here, we describe a mechanism that ensures rapid and selective long-range Cdc42-WASp recognition [38].
  • Although Cdc42, TC10, and other members of the Rho family have been implicated in binding to and activating the WAS proteins, the exact nature of such a protein-protein recognition process has remained obscure [38].
  • At the leading edge, Rac1 and Cdc42 promote cell motility through the formation of lamellipodia and filopodia, respectively [39].
  • The Rho family of small GTPases (RhoA, Rac1 and Cdc42) controls signal-transduction pathways that influence many aspects of cell behaviour, including cytoskeletal dynamics [39].
  • Our findings indicate that MCSP may modify tumour growth or invasion by a unique signal-transduction pathway that links Cdc42 activation to downstream tyrosine phosphorylation and subsequent cytoskeletal reorganization [13].

Analytical, diagnostic and therapeutic context of CDC42


  1. Flt-1-mediated down-regulation of endothelial cell proliferation through pertussis toxin-sensitive G proteins, beta gamma subunits, small GTPase CDC42, and partly by Rac-1. Zeng, H., Zhao, D., Mukhopadhyay, D. J. Biol. Chem. (2002) [Pubmed]
  2. CDC42 and Rac1 are implicated in the activation of the Nef-associated kinase and replication of HIV-1. Lu, X., Wu, X., Plemenitas, A., Yu, H., Sawai, E.T., Abo, A., Peterlin, B.M. Curr. Biol. (1996) [Pubmed]
  3. Adenovirus endocytosis requires actin cytoskeleton reorganization mediated by Rho family GTPases. Li, E., Stupack, D., Bokoch, G.M., Nemerow, G.R. J. Virol. (1998) [Pubmed]
  4. Signal therapy of breast cancers by the HDAC inhibitor FK228 that blocks the activation of PAK1 and abrogates the tamoxifen-resistance. Hirokawa, Y., Arnold, M., Nakajima, H., Zalcberg, J., Maruta, H. Cancer Biol. Ther. (2005) [Pubmed]
  5. Rho family GTPase Cdc42 is essential for the actin-based motility of Shigella in mammalian cells. Suzuki, T., Mimuro, H., Miki, H., Takenawa, T., Sasaki, T., Nakanishi, H., Takai, Y., Sasakawa, C. J. Exp. Med. (2000) [Pubmed]
  6. Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. Nod??-Langlois, R., Muller, D., Boda, B. J. Cell. Sci. (2006) [Pubmed]
  7. Individual differences in the in vitro response to cyclosporin A (CsA): possible heterogeneity in the involvement of the CD28-B7/BB1 pathway. Masy, E., Labalette-Houache, M., Dessaint, J.P. Thérapie. (1994) [Pubmed]
  8. Biology of the p21-activated kinases. Bokoch, G.M. Annu. Rev. Biochem. (2003) [Pubmed]
  9. Phosphoinositides Specify Polarity during Epithelial Organ Development. Comer, F.I., Parent, C.A. Cell (2007) [Pubmed]
  10. PTEN-Mediated Apical Segregation of Phosphoinositides Controls Epithelial Morphogenesis through Cdc42. Martin-Belmonte, F., Gassama, A., Datta, A., Yu, W., Rescher, U., Gerke, V., Mostov, K. Cell (2007) [Pubmed]
  11. A Rich1/Amot Complex Regulates the Cdc42 GTPase and Apical-Polarity Proteins in Epithelial Cells. Wells, C.D., Fawcett, J.P., Traweger, A., Yamanaka, Y., Goudreault, M., Elder, K., Kulkarni, S., Gish, G., Virag, C., Lim, C., Colwill, K., Starostine, A., Metalnikov, P., Pawson, T. Cell (2006) [Pubmed]
  12. Closing the GAP between Polarity and Vesicle Transport. Macara, I.G., Spang, A. Cell (2006) [Pubmed]
  13. Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130cas. Eisenmann, K.M., McCarthy, J.B., Simpson, M.A., Keely, P.J., Guan, J.L., Tachibana, K., Lim, L., Manser, E., Furcht, L.T., Iida, J. Nat. Cell Biol. (1999) [Pubmed]
  14. Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization. Leung, T., Chen, X.Q., Tan, I., Manser, E., Lim, L. Mol. Cell. Biol. (1998) [Pubmed]
  15. Characterization of rac and cdc42 activation in chemoattractant-stimulated human neutrophils using a novel assay for active GTPases. Benard, V., Bohl, B.P., Bokoch, G.M. J. Biol. Chem. (1999) [Pubmed]
  16. Cdc42 and RhoB activation are required for mannose receptor-mediated phagocytosis by human alveolar macrophages. Zhang, J., Zhu, J., Bu, X., Cushion, M., Kinane, T.B., Avraham, H., Koziel, H. Mol. Biol. Cell (2005) [Pubmed]
  17. Involvement of Cdc42 signaling in apoA-I-induced cholesterol efflux. Nofer, J.R., Feuerborn, R., Levkau, B., Sokoll, A., Seedorf, U., Assmann, G. J. Biol. Chem. (2003) [Pubmed]
  18. Glucose- and GTP-dependent stimulation of the carboxyl methylation of CDC42 in rodent and human pancreatic islets and pure beta cells. Evidence for an essential role of GTP-binding proteins in nutrient-induced insulin secretion. Kowluru, A., Seavey, S.E., Li, G., Sorenson, R.L., Weinhaus, A.J., Nesher, R., Rabaglia, M.E., Vadakekalam, J., Metz, S.A. J. Clin. Invest. (1996) [Pubmed]
  19. Fibronectin matrix regulates activation of RHO and CDC42 GTPases and cell cycle progression. Bourdoulous, S., Orend, G., MacKenna, D.A., Pasqualini, R., Ruoslahti, E. J. Cell Biol. (1998) [Pubmed]
  20. The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Li, X., Bu, X., Lu, B., Avraham, H., Flavell, R.A., Lim, B. Mol. Cell. Biol. (2002) [Pubmed]
  21. Cloning and expression of a human CDC42 GTPase-activating protein reveals a functional SH3-binding domain. Barfod, E.T., Zheng, Y., Kuang, W.J., Hart, M.J., Evans, T., Cerione, R.A., Ashkenazi, A. J. Biol. Chem. (1993) [Pubmed]
  22. Spreading of differentiating human monocytes is associated with a major increase in membrane-bound CDC42. Aepfelbacher, M., Vauti, F., Weber, P.C., Glomset, J.A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  23. Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils. Szczur, K., Xu, H., Atkinson, S., Zheng, Y., Filippi, M.D. Blood (2006) [Pubmed]
  24. Tyrosine phosphorylation of the Wiskott-Aldrich syndrome protein by Lyn and Btk is regulated by CDC42. Guinamard, R., Aspenström, P., Fougereau, M., Chavrier, P., Guillemot, J.C. FEBS Lett. (1998) [Pubmed]
  25. Phylogenetic and structural analysis of the Drosophila melanogaster p21-activated kinase DmPAK3. Mentzel, B., Raabe, T. Gene (2005) [Pubmed]
  26. Effector proteins exert an important influence on the signaling-active state of the small GTPase Cdc42. Phillips, M.J., Calero, G., Chan, B., Ramachandran, S., Cerione, R.A. J. Biol. Chem. (2008) [Pubmed]
  27. A phosphatidylinositol 3-kinase-independent insulin signaling pathway to N-WASP/Arp2/3/F-actin required for GLUT4 glucose transporter recycling. Jiang, Z.Y., Chawla, A., Bose, A., Way, M., Czech, M.P. J. Biol. Chem. (2002) [Pubmed]
  28. Cdc42 induces activation loop phosphorylation and membrane targeting of mixed lineage kinase 3. Du, Y., Böck, B.C., Schachter, K.A., Chao, M., Gallo, K.A. J. Biol. Chem. (2005) [Pubmed]
  29. Cdc42-interacting protein 4 mediates binding of the Wiskott-Aldrich syndrome protein to microtubules. Tian, L., Nelson, D.L., Stewart, D.M. J. Biol. Chem. (2000) [Pubmed]
  30. Evidence for a novel Cdc42GAP domain at the carboxyl terminus of BNIP-2. Low, B.C., Seow, K.T., Guy, G.R. J. Biol. Chem. (2000) [Pubmed]
  31. Activation of p21-CDC42/Rac-activated kinases by CD28 signaling: p21-activated kinase (PAK) and MEK kinase 1 (MEKK1) may mediate the interplay between CD3 and CD28 signals. Kaga, S., Ragg, S., Rogers, K.A., Ochi, A. J. Immunol. (1998) [Pubmed]
  32. Substrate specificity and recognition is conferred by the pleckstrin homology domain of the Dbl family guanine nucleotide exchange factor P-Rex2. Joseph, R.E., Norris, F.A. J. Biol. Chem. (2005) [Pubmed]
  33. Wiskott-Aldrich syndrome protein regulates podosomes in primary human macrophages. Linder, S., Nelson, D., Weiss, M., Aepfelbacher, M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  34. The role of SPECs, small Cdc42-binding proteins, in F-actin accumulation at the immunological synapse. Ching, K.H., Kisailus, A.E., Burbelo, P.D. J. Biol. Chem. (2005) [Pubmed]
  35. Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase. DerMardirossian, C., Schnelzer, A., Bokoch, G.M. Mol. Cell (2004) [Pubmed]
  36. Cdc42 downregulates MMP-1 expression by inhibiting the ERK1/2 pathway. Deroanne, C.F., Hamelryckx, D., Ho, T.T., Lambert, C.A., Catroux, P., Lapière, C.M., Nusgens, B.V. J. Cell. Sci. (2005) [Pubmed]
  37. Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathway. Huang, Q., Shen, H.M., Ong, C.N. Cell. Mol. Life Sci. (2005) [Pubmed]
  38. An electrostatic steering mechanism of Cdc42 recognition by Wiskott-Aldrich syndrome proteins. Hemsath, L., Dvorsky, R., Fiegen, D., Carlier, M.F., Ahmadian, M.R. Mol. Cell (2005) [Pubmed]
  39. Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Asanuma, K., Yanagida-Asanuma, E., Faul, C., Tomino, Y., Kim, K., Mundel, P. Nat. Cell Biol. (2006) [Pubmed]
  40. The Cdc42 and Rac1 GTPases are required for capillary lumen formation in three-dimensional extracellular matrices. Bayless, K.J., Davis, G.E. J. Cell. Sci. (2002) [Pubmed]
  41. Activation of Rac2 and Cdc42 on Fc and complement receptor ligation in human neutrophils. Forsberg, M., Druid, P., Zheng, L., Stendahl, O., Särndahl, E. J. Leukoc. Biol. (2003) [Pubmed]
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