Skip to main content
SpringerLink
Log in

Small GTPases of the Rho Family and Cell Transformation

  • Chapter
Cytoskeleton and Small G Proteins

Part of the book series: Progress in Molecular and Subcellular Biology ((PMSB,volume 22))

Abstract

The Rho GTPases form a distinct subgroup of the Ras superfamily of low molecular weight GTP binding proteins. These proteins are implicated in signal transduction leading to changes in membrane structures and cytoskeletal reorganisation associated with changes in cell shape. Like other Ras-related proteins, Rho GTPases are thought to adopt either an active GTP-bound conformational state or an inactive GDP-bound state. Although cycling between these states is controlled by several regulatory proteins, mutations in Rho proteins can favour a specific status: an asparagine substitution in Rho at a position homologous to Ras threonine 17leads to a drop in its affinity for GTP. This mutated protein acts as an inhibitor by sequestering positive regulatory factors, thereby preventing activation of the endogenous Rho GTPase. Conversely, substitutions of residues similar to those found in oncogenic Ras proteins (e.g. G12V or Q61L) leads to constitutively active Rho proteins, due to a reduced GTP hydrolysis. Once loaded with GTP, the GTPase gains the ability to bind cognate effector downstream targets, which converts the input signal into a specific set of activations.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abo A, Pick E, Hall A, Totty N, Teahan CG, Segal AW (1991) Activation of the NADPH oxidase involves the small GTP-binding protein p2lracl. Nature 353:668–670

    Article  PubMed  CAS  Google Scholar 

  • Abo A, Webb MR, Grogan A, Segal AW (1994) Activation of NADPH oxidase involves the dissociation of p2lrac from its inhibitory GDP/GTP exchange protein (rhoGDI) followed by its translocation to the plasma membrane. Biochem J 3:585–591

    Google Scholar 

  • Adams AE, Johnson DI, Longnecker RM, Sloat BF, Pringle JR (1990) CDC42 and CDC43, two additional genes involved in budding and the establishment of cell polarity in the yeast Saccharomyces cerevisiae. J Cell Biol 111:131–142

    Article  PubMed  CAS  Google Scholar 

  • Adra CN, Ko J, Leonard D, Wirth LJ, Cerione RA, Lim B (1993) Identification of a novel protein with GDP dissociation inhibitor activity for the ras-like proteins CDC42Hs and rac I. Genes Chromosom Cancer 8:253–261

    Article  PubMed  CAS  Google Scholar 

  • Adra CN, Manor D, Ko JL, Zhu S, Horiuchi T, Van Aelst L, Cerione RA, Lim B (1997) RhoGDlgamma: a GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas. Proc Natl Acad Sci USA 94:4279–4284

    Article  PubMed  CAS  Google Scholar 

  • Aepfelbacher M, Vauti F, Weber PC, Glomset JA (1994) Spreading of differentiating human monocytes is associated with a major increase in membrane-bound CDC42. Proc Natl Acad Sci USA 91:4263–4267

    Article  PubMed  CAS  Google Scholar 

  • Allen WE, Jones GE, Pollard JW, Ridley AJ (1997) Rho, Rac and Cdc42 regulate actin organization and cell adhesion in macrophages. J Cell Sci 110:707–720

    PubMed  CAS  Google Scholar 

  • Avraham H, Weinberg RA (1989) Characterization and expression of the human rhoH12 gene product. Mol Cell Biol 9:2058–2066

    PubMed  CAS  Google Scholar 

  • Bagrodia S, Derijard B, Davis RJ, Cerione RA (1995) Cdc42 and PAK-mediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation. J Biol Chem 270:27995–27998

    Article  PubMed  CAS  Google Scholar 

  • Bar-Sagi D, Feramisco JR (1986) Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins. Science 233:1061–1068

    Article  PubMed  CAS  Google Scholar 

  • Barfod ET, Zheng Y, Kuang WJ, Hart MJ, Evans T, Cerione RA, Ashkenazi A (1993) Cloning and expression of a human CDC42 GTPase-activating protein reveals a functional SH3-binding domain. J Biol Chem 268:26059–26062

    PubMed  CAS  Google Scholar 

  • Brenner B, Koppenhoefer U, Weinstock C, Linderkamp O, Lang F, Gulbins E (1997) Fas-or ceramide-induced apoptosis is medicated by a Racl-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153. J Biol Chem 272:22173–22181

    Article  PubMed  CAS  Google Scholar 

  • Brill S, Li S, Lyman CW, Church DM, Wasmuth JJ, Weissbach L, Bernards A, Snijders AJ (1996) The Ras GTPase-activating-protein-realted human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases. Mol Cell Biol 16:4869–4878

    PubMed  CAS  Google Scholar 

  • Brown JL, Stowers L, Baer M, Trejo J, Coughlin S, Chant J (1996) Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway. Curr Biol 6:598–605

    Article  PubMed  CAS  Google Scholar 

  • Bruhat A, Jousse C, Wang XZ, Ron D, Ferrara M, Fafournoux P (1997) Amino acid limitation induces expression of CHOP, a CCAAT/enhancer binding protein-related gene, at both transcriptional and post-transcriptional levels. J Biol Chem 272:17588–17593

    Article  PubMed  CAS  Google Scholar 

  • Burbelo PD, Miyamoto S, Utani A, Brill S, Yamada KM, Hall A, Yamada Y (1995) p190-B, a new member of the Rho GAP family, and Rho are induced to cluster after integrin cross-linking. J Biol Chem 270:30919–30926

    Google Scholar 

  • Cano E, Mahadevan LC (1995) Parallel signal processing among mammalian MAPKs. Trends Biochem Sci 20:117–122

    Article  PubMed  CAS  Google Scholar 

  • Cerione RA, Zheng Y (1996) The Dbl family of oncogenes. Curr Opin Cell Biol 8:216–222

    Article  PubMed  CAS  Google Scholar 

  • Chan AM, McGovern ES, Catalano G, Fleming TP, Miki T (1994) Expression cDNA cloning of novel oncogene with sequence similiarity to regulators of small GTP-binding proteins. Oncogene 9:1057–1063

    PubMed  CAS  Google Scholar 

  • Chang EC, Barr M, Wang Y, Jung V, Xu HP, Wigler MH (1994) Cooperative interaction of S. pombe proteins required for mating and morphogenesis. Cell 79:131–141

    Article  PubMed  CAS  Google Scholar 

  • Chardin P, Madaule P, Tavitian A (1988) Coding sequences of human rho cDNAs clone 6 and clone 9. Nucleic Acids Res 16:2717

    Article  PubMed  CAS  Google Scholar 

  • Cicchetti P, Ridley AJ, Zheng Y, Cerione RA, Baltimore D (1995) 3BP-1, an SH3 domain binding protein, has GAP activity for Rac and inhibits growth factor-induced membrane ruffling in fibroblasts. EMBO J 14:3127–3135

    PubMed  CAS  Google Scholar 

  • Cooper JA, Kashishian A (1993) In vivo binding properties of SH2 domains from GTPaseactivating protein and phosphatidylinositol 3-kinase. Mol Cell Biol 13:1737–1745

    PubMed  CAS  Google Scholar 

  • Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu NG, Miki T, Gutkind JS (1995) The small GTP-Binding proteins racl and cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 81:1137–1146

    Article  PubMed  CAS  Google Scholar 

  • Courjal F, Chuchana P, Theillet C, Fort P (1997) Structure and chromosomal assignment to 22q12 and 17gter of the ras-related Rac2 and Rac3 human genes. Genomics 44:242–246

    Article  PubMed  CAS  Google Scholar 

  • Dallery E, Galiegue-Zouitina S, Collyn-d’Hooghe M, Quief S, Denis C, Hildebrand MP, Lantoine D, Deweindt C, Tilly H, Bastard C (1995) TTF, a gene encoding a novel small G protein, fuses to the lymphoma-associated LAZ3 gene by t(3;4) chromosomal translocation. Oncogene 10:2171–2178

    PubMed  CAS  Google Scholar 

  • Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ (1994) JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76:1025–1037

    Article  PubMed  CAS  Google Scholar 

  • Didsbury J, Weber RF, Bokoch GM, Evans T, Synderman R (1989) rac, a novel ras-related family of proteins that are botulinum toxin substrates. J Biol Chem 264:16378–16382

    PubMed  CAS  Google Scholar 

  • Donovan FM, Pike CJ, Cotman CW, Cunningham DD (1997) Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities. J Neurosci 17:5316–5326

    PubMed  CAS  Google Scholar 

  • Drivas GT, Shih A, Coutavas E, Rush MG, D’Eustachio P (1990) Characterization of four novel ras-like genes expressed in a human teratocarcinoma cell line. Mol Cell Biol 10:1793–1798

    PubMed  CAS  Google Scholar 

  • Dutartre H, Davoust J, Gorvel J-P, Chavrier P (1996) Cytokinesis arrest and redistribution of actin-cytoskeleton regulatory components in cells expressing the Rho GTPase Cdc42Hs. J Cell Sci 109:367–377

    PubMed  CAS  Google Scholar 

  • Esteve P, del Peso L, Lacal JC (1995) Induction of apoptosis by rho in NIH 3T3 cells requires two complementary signals. Ceramides function as a progression factor for apoptosis. Oncogene 11:2657–2665

    PubMed  CAS  Google Scholar 

  • Evan G (1997) Cancer: a matter of life and and cell death. Int J Cancer 71:709–711

    Article  PubMed  CAS  Google Scholar 

  • Fanger GR, Lassignal-Johnson N, Johnson GL (1997) MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42. EMBO J 16:4961–4972

    Article  PubMed  CAS  Google Scholar 

  • Fishbein JD, Dobrowsky RT, Bielawska A, Garrett S, Hannun YA (1993) Ceramide-mediated growth inhibition and CAPP are conserved in Saccharomyces cerevisiae. J Biol Chem 268:9255–9261

    PubMed  CAS  Google Scholar 

  • Flescher EG, Madden K, Snyder M (1993) Components required for cytokinesis are important for bud site selection in yeast. J Cell Biol 122:373–386

    Article  PubMed  CAS  Google Scholar 

  • Foster R, Hu KQ, Lu Y, Nolan KM, Thissen J, Settleman J (1996) Identification of a novel human Rho protein with unusual properties: GTPase deficiency and in vivo farnesylation. Mol Cell Biol 16:2689–2699

    PubMed  CAS  Google Scholar 

  • Fukumoto Y, Kaibuchi K, Hori Y, Fujioka H, Araki S, Ueda T, Kikuchi A, Takai Y (1990) Molecular cloning and characterization of a novel type of regulatory protein (GDI) for the rho proteins, ras p21-like small GTP-binding proteins. Oncogene 5:1321–1328

    PubMed  CAS  Google Scholar 

  • Galley Y, Hagens G, Glaser I, Davis W, Eichhorn M, Dobbelaere D (1997) Jun NH2-terminal kinase is constitutively activated in T cells transformed by the intracellular parasite Theileria parva. Proc Natl Acad Sci USA 94:5119–5124

    Article  PubMed  CAS  Google Scholar 

  • Garrett MD, Major GN, Totty N, Hall A (1991) Purification and N-terminal sequence of the p2lrho GTPase-activating protein, rho GAP. Biochem J 276:833–836

    PubMed  CAS  Google Scholar 

  • Gerwins P, Blank JL, Johnson GL (1997) Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. J Biol Chem 272:8288–8295

    Article  PubMed  CAS  Google Scholar 

  • Gomez J, Martinez C, Fernandez B, Garcia A, Reboilo A (1997) Ras activation leads to cell proliferation or apoptotic cell death upon interleukin-2 stimulation or lymphokine deprivation, respectively (In Process Citation]. Eur J Immunol 27:1610–1618

    Article  PubMed  CAS  Google Scholar 

  • Gulbins E, Bissonnette R, Mahboubi A, Martin S, Nishioka W, Brunner T, Baier G, Baier-Bitterlich G, Byrd C, Lang F et al. (1995) FAS-induced apoptosis is mediated via a ceramideinitiated RAS signaling pathway. Immunity 2:341–351

    Article  PubMed  CAS  Google Scholar 

  • Gulbins E, Coggeshall KM, Brenner B, Schlottmann K, Linderkamp 0, Lang F (1996) Fas-induced apoptosis is mediated by activation of a Ras and Rac protein-regulated signaling pathway. J Biol Chem 271:26389–26394

    Article  PubMed  CAS  Google Scholar 

  • Haataja L, Groffen J, Heisterkamp N (1997) Characterization of RAC3, a novel member of the rho family. J Biol Chem 272:20384–20388

    Article  PubMed  CAS  Google Scholar 

  • Habets GG, Scholtes EH, Zuydgeest D, van der Kammen RA, Stam JC, Berns A, Collard JG (1994) Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Cell 77:537–549

    Article  PubMed  CAS  Google Scholar 

  • Hale AJ, Smith CA, Sutherland LC, Stoneman VE, Longthorne VL, Culhane AC, Williams GT (1996) Apoptosis: molecular regulation of cell death. Eur J Biochem 236:1–26

    Article  PubMed  CAS  Google Scholar 

  • Hall C, Monfries C, Smith P, Lim HH, Kozma R, Ahmed S, Vanniasingham V, Leung T, Lim L (1990) Novel human brain cDNA encoding a 34 000 Mr protein n-chimaerin, related to both the regulatory domain of protein kinase C and BCR, the product of the breakpoint cluster region gene. J Mol Biol 211:11–16

    Article  PubMed  CAS  Google Scholar 

  • Han J, Lee JD, Bibbs L, Ulevitch RJ (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265:808–811

    Article  PubMed  CAS  Google Scholar 

  • Hart MJ, Eva A, Evans T, Aaronson SA, Cerione RA (1991a) Catalysis of guanine nucleotide exchange on the CDC42Hs protein by the dbl oncogene product. Nature 354:311–314

    Article  PubMed  CAS  Google Scholar 

  • Hart MJ, Shinjo K, Hall A, Evans T, Cerione RA (1991b) Identification of the human platelet GTPase activating protein for the CDC42Hs protein. J Biol Chem 266:20840–20848

    PubMed  CAS  Google Scholar 

  • Hart MJ, Eva A, Zangrilli D, Aaronson SA, Evans T, Cerione RA, Zheng Y (1994) Cellular transformation and guanine nucleotide exchange activity are catalyzed by a common domain on the dbl oncogene product. J Biol Chem 269:62–65

    PubMed  CAS  Google Scholar 

  • Heisterkamp N, Stephenson JR, Groffen J, Hansen PF, de Klein A, Bartram CR, Grosveld G (1983) Localization of the c-abl oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature 306:239–242

    Article  PubMed  CAS  Google Scholar 

  • Heisterkamp N, Kaartinen V, van Soest S, Bokoch GM, Groffen J (1993) Human ABR encodes a protein with GAPrac activity and homology to the DBL nucleotide exchange factor domain. J Biol Chem 268:16903–16906

    PubMed  CAS  Google Scholar 

  • Henkemeyer M, Rossi DJ, Holmyard DP, Puri MC, Mbamalu G, Harpal K, Shih TS, Jacks T, Pawson T (1995) Vascular system defects and neuronal apoptosis in mice lacking ras GTPaseactivating protein. Nature 377:695–701

    Article  PubMed  CAS  Google Scholar 

  • Herskowitz I (1995) MAP kinase pathway in yeast: fore mating and more. Cell 80:187–197

    Article  PubMed  CAS  Google Scholar 

  • Hildebrand JD, Taylor JM, Parsons JT (1996) An SH3 domain-containing GTPase-activating protein for Rho and Cdc42 associates with focal adhesion kinase. Mol Cell Biol 16:3169–3178

    PubMed  CAS  Google Scholar 

  • Hill CS, Wynne J, Treisman R (1995) The rho family GTPases RhoA, racl, and CDC42Hs regulate transcriptional activation by SRF. Cell 81:1159–1170

    Article  PubMed  CAS  Google Scholar 

  • Hirata K, Kikuchi A, Sasaki T, Kuroda S, Kaibuchi K, Matsuura Y, Seki H, Saida K, Takai Y (1992) Involvement of rho p21 in the GTP-enhanced calcium ion sensitivity of smooth muscle contraction. J Biol Chem 267:8719–8722

    PubMed  CAS  Google Scholar 

  • Horii Y, Beeler JF, Sakaguchi K, Tachibana M, Miki T (1994) A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways. EMBO J 13:4776–4786

    PubMed  CAS  Google Scholar 

  • Jayadev S, Liu B, Bielawska AE, Lee JY, Nazaire F, Pushkareva M, Obeid LM, Hannun YA (1995) Role for ceramide in cell cycle arrest. J Biol Chem 270:2047–2052

    Article  PubMed  CAS  Google Scholar 

  • Jimenez B, Arends M, Esteve P, Perona R, Sanchez R, Ramon YSC, Wyllie A, Lacal JC (1995) Induction of apoptosis in NIH3T3 cells after serum deprivation by overexpression of rho-p21, a GTPase protein of the ras superfamily. Oncogene 10:811–816

    PubMed  CAS  Google Scholar 

  • Johnson DI, Pringle JR (1990) Molecular characterization of CDC42, a Saccharomyces cerevisiae gene involved in the development of cell polarity. J Cell Biol 111:143–152

    Article  PubMed  CAS  Google Scholar 

  • Joneson T, McDonough M, Bar-Sagi D, Van Aelst L (1996) RAC regulation of actin polymerization and proliferation by a pathway distinct from Jun kinase. Science 274:1374–1376

    Article  PubMed  CAS  Google Scholar 

  • Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH (1995) Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/ Rac GTPase-activating protein activity. J Biol Chem 270:22473–22477

    Article  PubMed  CAS  Google Scholar 

  • Katzav S, Martin-Zanca D, Barbacid M (1989) vav, a novel human oncogene derived from a locus ubiquitously expressed in hematopoietic cells. EMBO J 8:2283–2290

    PubMed  CAS  Google Scholar 

  • Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, Evan G (1997) Suppression of c-Myc-induced apoptosis by Ras signalling through PI (3)K and PKB. Nature 385:544–548

    Article  PubMed  CAS  Google Scholar 

  • Khosravi-Far R, Solski PA, Clark GJ, Kinch MS, Der CJ (1995) Activation of Rad, RhoA, and mitogen-activated protein kinases is required for Ras transformation. Mol Cell Biol 15:6443–6453

    PubMed  CAS  Google Scholar 

  • Khosravi-Far R, White MA, Westwick JK, Solski PA, Chrzanowska-Wodnicka M, Van Aelst L, Wigler MH, Der CJ (1996) Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol 16:3923–3933

    PubMed  CAS  Google Scholar 

  • Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J (1997) Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/ Akt cellular survival pathway. EMBO J 16:2783–2793

    Article  PubMed  CAS  Google Scholar 

  • Knaus UG, Heyworth PG, Evans T, Curnutte JT, Bokoch GM (1991) Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac 2. Science 254:1512–1515

    Article  PubMed  CAS  Google Scholar 

  • Knaus UG, Heyworth PG, Kinsella BT, Curnutte JT, Bokoch GM (1992) Purification and characterization of Rac 2. A cytosolic GTP-binding protein that regulates human neutrophil NADPH oxidase. J Biol Chem 267:23575–23582

    PubMed  CAS  Google Scholar 

  • Knaus UG, Morris S, Dong HJ, Chernoff J, Bokoch GM (1995) Regulation of human leukocyte p21-activated kinases through G protein-coupled receptors. Science 269:221–223

    Article  PubMed  CAS  Google Scholar 

  • Kyriakis JM, Avruch J (1996) Protein kinase cascades activated by stress and inflammatory cytokines. Bioessays 18:567–577.

    Article  PubMed  CAS  Google Scholar 

  • Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J, Woodgett JR (1994) The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369:156–160

    Article  PubMed  CAS  Google Scholar 

  • Lacal JC (1997) Regulation of proliferation and apoptosis by Ras and Rho GTPases through specific phospholipid-dependent signaling. FEBS Lett 410:73–77

    Article  PubMed  CAS  Google Scholar 

  • Lamarche N, Tapon N, Stowers L, Burbelo PD, Aspenstrom P, Bridges T, Chant J, Hall A (1996) Rac and Cdc42 induce actin polymerization and GI cell cycle progression independently of p65PAK and the JNK/SAPK MAP kinase cascade. Cell 87:519–529

    Article  PubMed  CAS  Google Scholar 

  • Lange-Carter CA, Pleiman CM, Gardner AM, Blumer KJ, Johnson GL (1993) A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science 260:315–319 Leevers SJ, Paterson HF, Marshall CJ (1994) Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 369:411–414

    Google Scholar 

  • Lim L, Manser E, Leung T, Hall C (1996) Regulation of phosphorylation pathways by p21 GTPases. The p21 Ras-related Rho subfamily and its role in phosphorylation signalling pathways. Eur J Biochem 242:171–185

    Article  PubMed  CAS  Google Scholar 

  • Lores P, Morin L, Luna R, Cacon G (1997) Enhanced apoptosis in the thymus of transgenic mice expressing constitutively activated forms of human Rac2GTPase. Oncogene 15:601–605

    Article  PubMed  CAS  Google Scholar 

  • Luo L, Liao YJ, Jan LY, Jan YN (1994) Distinct morphogenetic functions of similar small GTPases: Drosophila Dracl is involved in axonal outgrowth and myoblast fusion. Genes Dev 8:1787–1802

    Article  PubMed  CAS  Google Scholar 

  • Machesky L, Hall A (1996) Rho: a connection between membrane receptor signalling and the cytoskeleton. Trends Cell Biol 6:304–310

    Article  PubMed  CAS  Google Scholar 

  • Madaule P, Axel R (1985) A novel ras-related gene family. Cell 41:31–40

    Article  PubMed  CAS  Google Scholar 

  • Manser E, Leung T, Monfries C, Teo M, Hall C, Lim L (1992) Diversity and versatility of GTPase activating proteins for the p2lrho subfamily of ras G proteins detected by a novel overlay assay. J Biol Chem 267:16025–16028

    PubMed  CAS  Google Scholar 

  • Manser E, Chong C, Zhao ZS, Leung T, Michael G, Hall C, Lim L (1995) Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family. J Biol Chem 270:25070–25078

    Article  CAS  Google Scholar 

  • Manser E, Huang HY, Loo TH, Chen XQ, Dong JM, Leung T, Lim L (1997) Expression of constitutively active alpha-PAK reveals effects of the kinase on action and focal complexes. Mol Cell Biol 17:1129–1143

    PubMed  CAS  Google Scholar 

  • Marais R, Marshall CJ (1996) Control of the ERK MAP kinase cascade by Ras and Raf. Cancer Sury 27:101–125

    CAS  Google Scholar 

  • Marshall CJ (1996) Ras effectors. Curr Opin Cell Biol 8:197–204

    Article  CAS  Google Scholar 

  • Martin GA, Bollag G, McCormick F, Abo A (1995) A novel serine kinase activated by racl/ CDC42Hs-dependent autophosphorylation is related to PAK65 and STE20. EMBO J 14:1970–1978

    PubMed  CAS  Google Scholar 

  • Martin SJ, Green DR, Cotter TG (1994) Dicing with death: dissecting the components of the apoptosis machinery. Trends Biochem Sci 19:26–30

    Article  PubMed  CAS  Google Scholar 

  • Michiels F, Habets GG, Stam JC, van der Kammen RA, Collard JG (1995) A role for Rac in Tiamlinduced membrane ruffling and invasion. Nature 375:338–340

    Article  PubMed  CAS  Google Scholar 

  • Miki T, Smith CL, Long JE, Eva A, Fleming TP (1993) Oncogene ect2 is related to regulators of small GTP-binding proteins. Nature 362:462–465

    Article  PubMed  CAS  Google Scholar 

  • Minden A, Lin A, McMahon M, Lange CC, Derijard B, Davis RJ, Johnson GL, Karin M (1994) Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science 266:1719–1723

    Article  PubMed  CAS  Google Scholar 

  • Molnar A, Theodoras AM, Zon LI, Kyriakis JM (1997) Cdc42Hs, but not Racl, inhibits serum-stimulated cell cycle progression at G l /S through a mechanism requiring p38/RK. J Biol Chem 272:13229–13235

    Article  PubMed  CAS  Google Scholar 

  • Moorman JP, Bobak DA, Hahn CS (1996) Inactivation of the small GTP binding protein Rho induces multinucleate cell formation and apoptosis in murine T lymphoma EL4. J Immunol 156:4146–4153

    PubMed  CAS  Google Scholar 

  • Murphy AM, Montell DJ (1996) Cell type-specific roles for Cdc42, Rac, and RhoL in Drosophila oogenesis. J Cell Biol 133:617–630

    Article  PubMed  CAS  Google Scholar 

  • Murphy C, Saffrich R, Grummt M, Gournier H, Rybin V, Rubino M, Auvinen P, Lutcke A, Parton RG, Zerial M (1996) Endosome dynamics regulated by a Rho protein. Nature 384:427–432

    Article  PubMed  CAS  Google Scholar 

  • Nobes CD, Hall A (1995) Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81:53–62

    Article  PubMed  CAS  Google Scholar 

  • Obeid LM, Hannun YA (1995) Ceramide: a stress signal and mediator of growth suppression and apoptosis. J Cell Biochem 58:191–198

    Article  PubMed  CAS  Google Scholar 

  • Obeid LM, Linardic CM, Karolak LA, Hannun YA (1993) Programmed cell death induced by ceramide. Science 259:1769–1771

    Article  PubMed  CAS  Google Scholar 

  • Olson MF, Ashworth A, Hall A (1995) An essential role for rho, rac, and cdc42 GTPases in cell cycle progression through G1. Science 269:1270–1272

    Article  PubMed  CAS  Google Scholar 

  • Park SH, Weinberg RA (1995) A putative effector of Rat has homology to Rho/Rac GTPase activating proteins. Oncogene 11:2349–2355

    PubMed  CAS  Google Scholar 

  • Pasteris NG, Cadle A, Logie LJ, Porteous ME, Schwartz CE, Stevenson RE, Glover TW, Wilroy RS, Gorski JL (1994) Isolation and characterization of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: a putative Rho/Rac guanine nucleotide exchange factor. Cell 79:669–678

    Article  PubMed  CAS  Google Scholar 

  • Perona R, Esteve P, Jimenez B, Ballestero RP, Ramon Y, Cajal S, Lacal JC (1993) Tumorigenic activity of rho genes from Aplysia californica. Oncogene 8:1285–1292

    PubMed  CAS  Google Scholar 

  • Prendergast GC, Khosravi-Far R, Solski PA, Kurzawa H, Lebowitz PF, Der CI (1995) Critical role of Rho in cell transformation by oncogenic Ras. Oncogene 10:2289–2296

    PubMed  CAS  Google Scholar 

  • Pronk GJ, de Vries-Smits AM, Ellis C, Bos JL (1993) Complex formation between the p2lras GTPase-activating protein and phosphoproteins p62 and p190 is independent of p2lras signalling. Oncogene 8:2773–2780

    PubMed  CAS  Google Scholar 

  • Qiu R-G, Chen J, Kirn D, McCormick F, Symons M (1995a) An essential role for Rac in Ras transformation. Nature 374:457–459

    Article  PubMed  CAS  Google Scholar 

  • Qiu RG, Chen J, McCormick F, Symons M (1995b) A role for Rho in Ras transformation. Proc Natl Acad Sci USA 92:11781–11785

    Article  PubMed  CAS  Google Scholar 

  • Qiu RG, Abo A, McCormick F, Symons M (1997) Cdc42 regulates anchorage-independent growth and is necessary for Ras transformation. Mol Cell Biol 17:3449–3458

    PubMed  CAS  Google Scholar 

  • Raitano AB, Halpern JR, Hambuch TM, Sawyers CL (1995) The Bcr-Abl leukemia oncogene activates Jun kinase and requires Jun for transformation. Proc Natl Acad Sci USA 92:1174611750

    Google Scholar 

  • Reinhard J, Scheel AA, Diekmann D, Hall A, Ruppert C, Bahler M (1995) A novel type of myosin implicated in signalling by rho family GTPases. EMBO J 14:697–704

    PubMed  CAS  Google Scholar 

  • Ridley AJ (1994) Membrane ruffling and signal transduction. Bioessays 16:321–327

    Article  PubMed  CAS  Google Scholar 

  • Ridley AJ, Hall A (1992) The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70:389–399

    Article  PubMed  CAS  Google Scholar 

  • Ridley AJ, Paterson HF, Johnston CL, Diekmann IJ, Hall A (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70:401–410

    Article  PubMed  CAS  Google Scholar 

  • Ridley AJ, Self AJ, Kasmi F, Paterson HF, Hall A, Marshall CJ, Ellis C (1993) rho family GTPase activating proteins p190, bcr and rhoGAP show distinct specificities in vitro and in vivo. EMBO J 12:5151–5160

    PubMed  CAS  Google Scholar 

  • Rodrigues GA, Park M, Schlessinger J (1997) Activation of the JNK pathway is essential for transformation by the Met oncogene. EMBO J 16:2634–2645

    Article  PubMed  CAS  Google Scholar 

  • Ron D, Zannini M, Lewis M, Wickner RB, Hunt LT, Graziani G, Tronick SR, Aaronson SA, Eva A (1991) A region of proto-dbl essential for its transforming activity shows sequence similarity to a yeast cell cycle gene, CDC24, and the human breakpoint cluster gene, bcr. New Biol 3:372–379

    PubMed  CAS  Google Scholar 

  • Roux P, Gauthier-Rouvière C, Doucet-Brutin S, Fort P (1997) The small GTPases Cdc42Hs, Rac1 and RhoG delineate Raf-independent pathways that cooperate to transform NIH3T3 cells. Curr Biol 7:629–637

    Article  PubMed  CAS  Google Scholar 

  • Scherle P, Behrens T, Staudt LM (1993) Ly-GDI, a GDP-dissociation inhibitor of the RhoA GTP-binding protein, is expressed preferentially in lymphocytes. Proc Natl Acad Sci USA 90:7568–7572

    Article  PubMed  CAS  Google Scholar 

  • Sells MA, Knaus UG, Bagrodia S, Ambrose DM, Bokoch GM, Chernoff J (1997) Human p21-activated kinase (PAK1) regulates actin organization in mammalian cells. Curr Biol 7:202–210

    Article  PubMed  CAS  Google Scholar 

  • Settleman J, Narasimhan V, Foster LC, Weinberg RA (1992) Molecular cloning of cDNAs encoding the GAP-associated protein p190: implications for a signaling pathway from ras to the nucleus. Cell 69:539–549

    Article  PubMed  CAS  Google Scholar 

  • Shinjo K, Koland JG, Hart MJ, Narasimhan V, Johnson DI, Evans T, Cerione RA (1990) 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. Proc Natl Acad Sci USA 87:9853–9857.

    Article  PubMed  CAS  Google Scholar 

  • Stowers L, Yelon D, Berg LJ, Chant J (1995) Regulation of the polarization of T cells toward antigen-presenting cells by Ras-related GTPase CDC42. Proc Natl Acad Sci USA 92:5027–5031

    Article  PubMed  CAS  Google Scholar 

  • Tang Y, Chen Z, Ambrose D, Liu J, Gibbs JB, Chernoff J, Field J (1997) Kinase-deficient Pak1 mutants inhibit Ras transformation of Rat-1 fibroblasts. Mol Cell Biol 17:4454–4464

    PubMed  CAS  Google Scholar 

  • Tapon N, Hall A (1997) Rho, Rac and Cdc42 GTPases regulate the organization of the actin cytoskeleton. Curr Opin Cell Biol 9:86–92

    Article  PubMed  CAS  Google Scholar 

  • Teo M, Manser E, Lim L (1995) Identification and molecular cloning of a p21cdc42/racl -activated serine/threonine kinase that is rapidly activated by thrombin in platelets. J Biol Chem 270:26690–26697

    Article  PubMed  CAS  Google Scholar 

  • Teramoto H, Coso OA, Miyata H, Igishi T, Miki T, Gutkind JS (1996) Signaling from the small GTP-binding proteins Racl and Cdc42 to the c-Jun N-terminal kinase/stress-activated protein kinase pathway. A role for mixed lineage kinase 3/protein-tyrosine kinase 1, a novel member of the mixed lineage kinase family. J Biol Chem 271:27225–27228

    Article  PubMed  CAS  Google Scholar 

  • Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462

    Article  PubMed  CAS  Google Scholar 

  • Tibbles LA, Ing YL, Kiefer F, Chan J, Iscove N, Woodgett JR, Lassam NJ (1996) MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6. EMBO J 15:7026–7035

    PubMed  CAS  Google Scholar 

  • Toksoz D, Williams DA (1994) Novel human oncogene lbc detected by transfection with distinct homology regions to signal transduction products. Oncogene 9:621–628

    PubMed  CAS  Google Scholar 

  • Tribioli C, Droetto S, Bione S, Cesareni G, Torrisi MR, Lotti LV, Lanfrancone L, Toniolo D, Pelicci P (1996) An X chromosome-linked gene encoding a protein with characteristics of a rhoGAP predominantly expressed in hematopoietic cells. Proc Natl Acad Sci USA 93:695–699

    Article  PubMed  CAS  Google Scholar 

  • Van Aelst L, Joneson T, Bar-Sagi D (1996) Identification of a novel Racl interacting protein involved in membrane ruffling.

    Google Scholar 

  • van Leeuwen FN, van der Kammen RA, Habets GG, Collard JG (1995) Oncogenic activity of Tiaml and Racl in NIH3T3 cells. Oncogene 11:2215–2221

    PubMed  Google Scholar 

  • Verheij M, Bose R, Lin XH, Yao B, Jarvis WD, Grant S, Birrer MJ, Szabo E, Zon LI, Kyriakis JM et al. (1996) Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 380:75–79

    Article  PubMed  CAS  Google Scholar 

  • Vincent S, Jeanteur P, Fort P (1992) Growth-regulated expression of rhoG, a new member of the ras homolog gene family. Mol Cell Biol 12:3138–3148

    PubMed  CAS  Google Scholar 

  • Wang DZ, Nur-E-Kamal MS, Tikoo A, Montague W, Maruta H (1997) The GTPase and Rho GAP domains of p190, a tumor suppressor protein that binds the Mr 120000 Ras GAP, independently function as anti-Ras tumor suppressors. Cancer Res 57:2478–2484

    PubMed  CAS  Google Scholar 

  • Wang XZ, Lawson B, Brewer JW, Zinszner H, Sanjay A, Mi LJ, Boorstein R, Kreibich G, Hendershot LM, Ron D (1996) Signals from the stressed endoplasmic reticulum induce CI EBP-homologous protein (CHOP/GADD153). Mol Cell Biol 16:4273–4280

    PubMed  CAS  Google Scholar 

  • Westwick JK, Lambert QT, Clark GJ, Symons M, Van Aelst L, Pestell RG, Der CJ (1997) Rac regulation of transformation, gene expression, and actin organization by multiple, PAKindependent pathways. Mol Cell Biol 17:1324–1335

    PubMed  CAS  Google Scholar 

  • Whitehead I, Kirk H, Kay R (1995a) Retroviral transduction and oncogenic selection of a cDNA encoding Dbs, a homolog of the Dbl guanine nucleotide exchange factor. Oncogene 10:713721

    Google Scholar 

  • Whitehead I, Kirk H, Tognon C, Trigo-Gonzalez G, Kay R (1995b) Expression cloning of lfc, a novel oncogene with structural similarities to guanine nucleotide exchange factors and to the regulatory region of protein kinase C. J Biol Chem 270:18388–18395

    Article  PubMed  CAS  Google Scholar 

  • Whitehead IP, Khosravi-Far R, Kirk H, Trigo-Gonzalez G, Der CJ, Kay R (1996) Expression cloning of lsc, a novel oncogene with structural similarities to the Dbl family of guanine nucleotide exchange factors. J Biol Chem 271:18643–18650

    Article  PubMed  CAS  Google Scholar 

  • Wirth JA, Jensen KA, Post PL, Bement WM, Mooseker MS (1996) Human myosin-IXb, an unconventional myosin with a chimerin-like rho/rac GTPase-activating protein domain in its tail. J Cell Sci 109:653–661

    PubMed  CAS  Google Scholar 

  • Xu X, Heidenreich O, Kitajima I, McGuire K, Li Q, Su B, Nerenberg M (1996) Constitutively activated JNK is associated with HTLV-1 mediated tumorigenesis. Oncogene 13:135–142

    PubMed  CAS  Google Scholar 

  • Zalcman G, Closson V, Camonis J, Honore N, Rousseau-Merck MF, Tavitian A, Olofsson B (1996) RhoGDI-3 is a new GDP dissociation inhibitor (GDI). Identification of a non-cytosolic GDI protein interacting with the small GTP-binding proteins RhoB and RhoG. J Biol Chem 271:30366–30374

    Article  PubMed  CAS  Google Scholar 

  • Zheng Y, Cerione R, Bender A (1994) Control of the yeast bud-site assembly GTPase Cdc42. Catalysis of guanine nucleotide exchange by Cdc24 and stimulation of GTPase activity by Bem3. J Biol Chem 269:2369–2372

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut de Génétique Moléculaire de Montpellier, UMR, CNRS 5535, 1919, route de Mende, F-34293, Montpellier, cedex 05, France

    Philippe Fort

Authors
  1. Philippe Fort
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute of Molecular Genetics of Montpellier CNRS, University of Montpellier II, 1919 Route de Mende, Montpellier Cedex 5, F-34293, France

    Philippe Jeanteur

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Fort, P. (1999). Small GTPases of the Rho Family and Cell Transformation. In: Jeanteur, P. (eds) Cytoskeleton and Small G Proteins. Progress in Molecular and Subcellular Biology, vol 22. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-58591-3_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-58591-3_8

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-63659-2

  • Online ISBN: 978-3-642-58591-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation