Experimental Hematology
Volume 34, Issue 8 , Pages 976-985 , August 2006

The role of chemokine activation of Rac GTPases in hematopoietic stem cell marrow homing, retention, and peripheral mobilization

  • Jose A. Cancelas

      Affiliations

    • Division of Experimental Hematology, Cincinnati Children's Research Foundation, Cincinnati, Ohio, USA
    • Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  • ,
  • Michael Jansen

      Affiliations

    • Division of Experimental Hematology, Cincinnati Children's Research Foundation, Cincinnati, Ohio, USA
  • ,
  • David A. Williams

      Affiliations

    • Division of Experimental Hematology, Cincinnati Children's Research Foundation, Cincinnati, Ohio, USA
    • Corresponding Author InformationOffprint requests to: David A. Williams, M.D., Division of Experimental Hematology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, ML 7013, Cincinnati, OH 45215

References 

  1. Morrison SJ, Uchida N, Weissman IL. The biology of hematopoietic stem cells. Annu Rev Cell Dev Biol. 1995;11:35–71
  2. Kessinger A, Sharp JG. The whys and hows of hematopoietic progenitor and stem cell mobilization. Bone Marrow Transplant. 2003;31:319–329
  3. Sola C, Maroto P, Salazar R, et al. Bone marrow transplantation: prognostic factors of peripheral blood stem cell mobilization with cyclophosphamide and filgrastim (r-metHuG- CSF): The CD34+ cell dose positively affects the time to hematopoietic recovery and supportive requirements after high-dose chemotherapy. Hematology. 1999;4:195–209
  4. Salazar R, Sola C, Maroto P, et al. Infectious complications in 126 patients treated with high-dose chemotherapy and autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 1999;23:27–33
  5. Cancelas JA, Hernandez-Jodra M, Zamora C, et al. Circulating stem cell collection in lymphoma and myeloma after mobilization with cyclophosphamide and granulocyte colony-stimulating factor for autologous transplantation. Vox Sang. 1994;67:362–367
  6. Briddell RA, Hartley CA, Smith KA, McNiece IK. Recombinant rat stem cell factor synergizes with recombinant human granulocyte colony-stimulating factor in vivo in mice to mobilize peripheral blood progenitor cells that have enhanced repopulating potential. Blood. 1993;82:1720–1723
  7. Devine SM, Flomenberg N, Vesole DH, et al. Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma. J Clin Oncol. 2004;22:1095–1102
  8. Boque C, Petit J, Sarra J, et al. Mobilization of peripheral stem cells with intensive chemotherapy (ICE regimen) and G-CSF in chronic myeloid leukemia. Bone Marrow Transplant. 1996;18:879–884
  9. Cancelas JA, Querol S, Canals C, et al. Peripheral blood CD34+ cell immunomagnetic selection in breast cancer patients: effect on hematopoietic progenitor content and hematologic recovery after high-dose chemotherapy and autotransplantation. Transfusion. 1998;38:1063–1070
  10. Martinez C, Sureda A, Martino R, et al. Efficient peripheral blood stem cell mobilization with low-dose G-CSF (50 microg/m2) after salvage chemotherapy for lymphoma. Bone Marrow Transplant. 1997;20:855–858
  11. Petit J, Boque C, Cancelas JA, et al. Feasibility of ESHAP + G-CSF as peripheral blood hematopoietic progenitor cell mobilisation regimen in resistant and relapsed lymphoma: a single-center study of 22 patients. Leuk Lymphoma. 1999;34:119–127
  12. Graham RM, Bishopric NH, Webster KA. Gene and cell therapy for heart disease. IUBMB Life. 2002;54:59–66
  13. Wagner JE, Broxmeyer HE, Byrd RL, et al. Transplantation of umbilical cord blood after myeloablative therapy: analysis of engraftment. Blood. 1992;79:1874–1881
  14. Wagner JE, Barker JN, DeFor TE, et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 2002;100:1611–1618
  15. Gluckman E, Locatelli F. Umbilical cord blood transplants. Curr Opin Hematol. 2000;7:353–357
  16. Gluckman E, Rocha V, Chevret S. Results of unrelated umbilical cord blood hematopoietic stem cell transplantation. Rev Clin Exp Hematol. 2001;5:87–99
  17. Gluckman E. Current status of umbilical cord blood hematopoietic stem cell transplantation. Exp Hematol. 2000;28:1197–1205
  18. Yeh ET, Zhang S, Wu HD, Korbling M, Willerson JT, Estrov Z. Transdifferentiation of human peripheral blood CD34+-enriched cell population into cardiomyocytes, endothelial cells, and smooth muscle cells in vivo. Circulation. 2003;108:2070–2073
  19. Korbling M, Estrov Z. Adult stem cells for tissue repair—a new therapeutic concept?. N Engl J Med. 2003;349:570–582
  20. Hennessy B, Korbling M, Estrov Z. Circulating stem cells and tissue repair. Panminerva Med. 2004;46:1–11
  21. Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature. 2004;428:668–673
  22. Murry CE, Soonpaa MH, Reinecke H, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature. 2004;428:664–668
  23. Arai AE, Sheikh F, Agyeman KO, et al. Lack of benefit from cytokine mobilized stem cell therapy for acute myocardial infarction in nonhuman primates. J Am Coll Cardiol. 2002;41:335
  24. Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science. 1996;272:60–66
  25. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994;76:301–314
  26. Peled A, Grabovsky V, Habler L, et al. The chemokine SDF-1 stimulates integrin-mediated arrest of CD34+ cells on vascular endothelium under shear flow. J Clin Invest. 1999;104:1199–1211
  27. Gong JK. Endosteal marrow: a rich source of hematopoietic stem cells. Science. 1978;199:1443–1445
  28. Nilsson SK, Johnston HM, Coverdale JA. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood. 2001;97:2293–2299
  29. Driessen RL, Johnston HM, Nilsson SK. Membrane-bound stem cell factor is a key regulator in the initial lodgment of stem cells within the endosteal marrow region. Exp Hematol. 2003;31:1284–1291
  30. Williams DA, Rios M, Stephens C, Patel VP. Fibronectin and VLA-4 in haematopoietic stem cell–microenvironment interactions. Nature. 1991;352:438–441
  31. Williams DE, Fletcher FA, Lyman SD, de Vries P. Cytokine regulation of hematopoietic stem cells. Semin Immunol. 1991;3:391–396
  32. Papayannopoulou T, Priestley GV, Nakamoto B, Zafiropoulos V, Scott LM. Molecular pathways in bone marrow homing: dominant role of α4β1 over β2-integrins and selectins. Blood. 2001;98:2403–2411
  33. Papayannopoulou T. Bone marrow homing: the players, the playfield, and their evolving roles. Curr Opin Hematol. 2003;10:214–219
  34. Lapidot T, Kollet O. The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia. 2002;16:1992–2003
  35. Nagasawa T, Tachibana K, Kishimoto T. A novel CXC chemokine PBSF/SDF-1 and its receptor CXCR4: their functions in development, hematopoiesis and HIV infection. Semin Immunol. 1998;10:179–185
  36. Wright DE, Bowman EP, Wagers AJ, Butcher EC, Weissman IL. Hematopoietic stem cells are uniquely selective in their migratory response to chemokines. J Exp Med. 2002;195:1145–1154
  37. Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med. 1997;185:111–120
  38. Lataillade JJ, Clay D, Dupuy C, et al. Chemokine SDF-1 enhances circulating CD34+ cell proliferation in synergy with cytokines: possible role in progenitor survival. Blood. 2000;95:756–768
  39. Broxmeyer HE, Kohli L, Kim CH, et al. Stromal cell–derived factor-1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cells through CXCR4 and Gαi proteins and enhances engraftment of competitive, repopulating stem cells. J Leukoc Biol. 2003;73:630–638
  40. Peled A, Kollet O, Ponomaryov T, et al. The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34+ cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice. Blood. 2000;95:3289–3296
  41. Kollet O, Spiegel A, Peled A, et al. Rapid and efficient homing of human CD34+CD38−/lowCXCR4+ stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2mnull mice. Blood. 2001;97:3283–3291
  42. Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999;283:845–848
  43. Ma Q, Jones D, Springer TA. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity. 1999;10:463–471
  44. Nagasawa T, Hirota S, Tachibana K, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996;382:635–638
  45. Miyazawa K, Williams DA, Gotoh A, Nishimaki J, Broxmeyer HE, Toyama K. Membrane-bound Steel factor induces more persistent tyrosine kinase activation and longer life span of c-kit gene-encoded protein than its soluble form. Blood. 1995;85:641–649
  46. Papayannopoulou T, Craddock C, Nakamoto B, Priestley GV, Wolf NS. The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen. Proc Natl Acad Sci U S A. 1995;92:9647–9651
  47. Papayannopoulou T, Craddock C. Homing and trafficking of hemopoietic progenitor cells. Acta Haematol. 1997;97:97–104
  48. Scott LM, Priestley GV, Papayannopoulou T. Deletion of α4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing. Mol Cell Biol. 2003;23:9349–9360
  49. Thomas J, Liu F, Link DC. Mechanisms of mobilization of hematopoietic progenitors with granulocyte colony-stimulating factor. Curr Opin Hematol. 2002;9:183–189
  50. Rafii S, Heissig B, Hattori K. Efficient mobilization and recruitment of marrow-derived endothelial and hematopoietic stem cells by adenoviral vectors expressing angiogenic factors. Gene Ther. 2002;9:631–641
  51. Kronenwett R, Martin S, Haas R. The role of cytokines and adhesion molecules for mobilization of peripheral blood stem cells. Stem Cells. 2000;18:320–330
  52. Wang J, Kimura T, Asada R, et al. SCID-repopulating cell activity of human cord blood–derived CD34 cells assured by intra–bone marrow injection. Blood. 2003;101:2924–2931
  53. Wright DE, Wagers AJ, Gulati AP, Johnson FL, Weissman IL. Physiological migration of hematopoietic stem and progenitor cells. Science. 2001;294:1933–1936
  54. Warren S, Chute RN, Farrington EM. Protection of the hematopoietic system by parabiosis. Lab Invest. 1960;9:191–198
  55. Abkowitz JL, Robinson AE, Kale S, Long MW, Chen J. The mobilization of hematopoietic stem cells during homeostasis and after cytokine exposure. Blood. 2003;102:1249–1253
  56. Sweeney EA, Papayannopoulou T. Increase in circulating SDF-1 after treatment with sulfated glycans. The role of SDF-1 in mobilization. Ann N Y Acad Sci. 2001;938:48–52
  57. Hattori K, Heissig B, Tashiro K, et al. Plasma elevation of stromal cell–derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood. 2001;97:3354–3360
  58. Sweeney EA, Lortat-Jacob H, Priestley GV, Nakamoto B, Papayannopoulou T. Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells. Blood. 2002;99:44–51
  59. Tavor S, Petit I, Porozov S, et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Res. 2004;64:2817–2824
  60. Liles WC, Broxmeyer HE, Rodger E, et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood. 2003;102:2728–2730
  61. Papayannopoulou T, Priestley GV, Bonig H, Nakamoto B. The role of G-protein signaling in hematopoietic stem/progenitor cell mobilization. Blood. 2003;101:4739–4747
  62. Papayannopoulou T, Priestley GV, Nakamoto B, Zafiropoulos V, Scott LM, Harlan JM. Synergistic mobilization of hemopoietic progenitor cells using concurrent β1 and β2 integrin blockade or β2-deficient mice. Blood. 2001;97:1282–1288
  63. Craddock CF, Nakamoto B, Andrews RG, Priestley GV, Papayannopoulou T. Antibodies to VLA4 integrin mobilize long-term repopulating cells and augment cytokine-induced mobilization in primates and mice. Blood. 1997;90:4779–4788
  64. Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 2002;109:625–637
  65. Levesque JP, Hendy J, Winkler IG, Takamatsu Y, Simmons PJ. Granulocyte colony-stimulating factor induces the release in the bone marrow of proteases that cleave c-kit receptor (CD117) from the surface of hematopoietic progenitor cells. Exp Hematol. 2003;31:109–117
  66. McNiece IK, Briddell RA. Stem cell factor. J Leukoc Biol. 1995;58:14–22
  67. Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992;70:389–399
  68. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A. The small GTP-binding protein rac regulates growth factor–induced membrane ruffling. Cell. 1992;70:401–410
  69. Aspenstrom P, Fransson A, Saras J. Rho GTPases have diverse effects on the organization of the actin filament system. Biochem J. 2004;377:327–337
  70. Zheng Y. Dbl family guanine nucleotide exchange factors. Trends Biochem Sci. 2001;26:724–732
  71. Timokhina I, Kissel H, Stella G, Besmer P. Kit signaling through PI 3-kinase and Src kinase pathways: an essential role for Rac1 and JNK activation in mast cell proliferation. EMBO J. 1998;17:6250–6262
  72. Taylor ML, Metcalfe DD. Kit signal transduction. Hematol Oncol Clin North Am. 2000;14:517–535
  73. del Pozo MA, Vicente-Manzanares M, Tejedor R, Serrador JM, Sanchez-Madrid F. Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes. Eur J Immunol. 1999;29:3609–3620
  74. del Pozo MA, Alderson NB, Kiosses WB, Chiang HH, Anderson RG, Schwartz MA. Integrins regulate Rac targeting by internalization of membrane domains. Science. 2004;303:839–842
  75. Alai M, Mui AL, Cutler RL, Bustelo XR, Barbacid M, Krystal G. Steel factor stimulates the tyrosine phosphorylation of the proto-oncogene product, p95vav, in human hemopoietic cells. J Biol Chem. 1992;267:18021–18025
  76. Gu Y, Filippi MD, Cancelas JA, et al. Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science. 2003;302:445–449
  77. Tan BL, Yazicioglu MN, Ingram D, et al. Genetic evidence for convergence of c-Kit- and α4 integrin-mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells. Blood. 2003;101:4725–4732
  78. Reibel L, Dorseuil O, Stancou R, Bertoglio J, Gacon G. A hemopoietic specific gene encoding a small GTP binding protein is overexpressed during T cell activation. Biochem Biophys Res Commun. 1991;175:451–458
  79. Bolis A, Corbetta S, Cioce A, de Curtis I. Differential distribution of Rac1 and Rac3 GTPases in the developing mouse brain: implications for a role of Rac3 in Purkinje cell differentiation. Eur J Neurosci. 2003;18:2417–2424
  80. Nishita M, Aizawa H, Mizuno K. Stromal cell–derived factor 1α activates LIM kinase 1 and induces cofilin phosphorylation for T-cell chemotaxis. Mol Cell Biol. 2002;22:774–783
  81. Whetton AD, Lu Y, Pierce A, Carney L, Spooncer E. Lysophospholipids synergistically promote primitive hematopoietic cell chemotaxis via a mechanism involving Vav 1. Blood. 2003;102:2798–2802
  82. van Hennik PB, ten Klooster JP, Halstead JR, et al. The C-terminal domain of Rac1 contains two motifs that control targeting and signaling specificity. J Biol Chem. 2003;278:39166–39175
  83. Vicente-Manzanares M, Cruz-Adalia A, Martin-Cofreces NB, et al. Control of lymphocyte shape and the chemotactic response by the GTP exchange factor Vav. Blood. 2005;105:3026–3034
  84. Roberts AW, Kim C, Zhen L, et al. Deficiency of the hematopoietic cell–specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense. Immunity. 1999;10:183–196
  85. Filippi MD, Harris CE, Meller J, Gu Y, Zheng Y, Williams DA. Localization of Rac2 via the C terminus and aspartic acid 150 specifies superoxide generation, actin polarity and chemotaxis in neutrophils. Nat Immunol. 2004;5:744–751
  86. Fulkerson PC, Zhu H, Williams DA, Zimmermann N, Rothenberg ME. CXCL9 inhibits eosinophil responses by a CCR3- and Rac2-dependent mechanism. Blood. 2005;106:436–443
  87. Walmsley MJ, Ooi SK, Reynolds LF, et al. Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling. Science. 2003;302:459–462
  88. Croker BA, Handman E, Hayball JD, et al. Rac2-deficient mice display perturbed T-cell distribution and chemotaxis, but only minor abnormalities in T(H)1 responses. Immunol Cell Biol. 2002;80:231–240
  89. Li B, Yu H, Zheng W, et al. Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. Science. 2000;288:2219–2222
  90. Gu Y, Byrne MC, Paranavitana NC, et al. (2002) Rac2, a hematopoiesis-specific Rho GTPase, specifically regulates mast cell protease gene expression in bone marrow–derived mast cells. Mol Cell Biol. 2002;22:7645–7657
  91. Yang FC, Kapur R, King AJ, et al. Rac2 stimulates Akt activation affecting BAD/Bcl-XL expression while mediating survival and actin function in primary mast cells. Immunity. 2000;12:557–568
  92. Cancelas JA, Lee AW, Prabhakar R, Stringer KF, Zheng Y, Williams DA. Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization. Nat Med. 2005;11:886–891
  93. Jansen M, Yang FC, Cancelas JA, Bailey JR, Williams DA. Rac2-deficient hematopoietic stem cells show defective interaction with the hematopoietic microenvironment and long-term engraftment failure. Stem Cells. 2005;23:335–346
  94. Yang FC, Atkinson SJ, Gu Y, et al. Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization. Proc Natl Acad Sci U S A. 2001;98:5614–5618
  95. Papayannopoulou T, Nakamoto B. Peripheralization of hemopoietic progenitors in primates treated with anti-VLA4 integrin. Proc Natl Acad Sci U S A. 1993;90:9374–9378
  96. Sander EE, ten Klooster JP, van Delft S, van der Kammen RA, Collard JG. Rac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J Cell Biol. 1999;147:1009–1022
  97. Moorman JP, Luu D, Wickham J, Bobak DA, Hahn CS. A balance of signaling by Rho family small GTPases RhoA, Rac1 and Cdc42 coordinates cytoskeletal morphology but not cell survival. Oncogene. 1999;18:47–57
  98. Ploemacher RE, van der Sluijs JP, van Beurden CA, Baert MR, Chan PL. Use of limiting-dilution type long-term marrow cultures in frequency analysis of marrow-repopulating and spleen colony–forming hematopoietic stem cells in the mouse. Blood. 1991;78:2527–2533
  99. Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A. 2004;101:7618–7623
  100. Diekmann D, Hall A. In vitro binding assay for interactions of Rho and Rac with GTPase-activating proteins and effectors. Methods Enzymol. 1995;256:207–215
  101. Moll J, Sansig G, Fattori E, van der Putten H. The murine rac1 gene: cDNA cloning, tissue distribution and regulated expression of rac1 mRNA by disassembly of actin microfilaments. Oncogene. 1991;6:863–866
  102. Didsbury J, Weber RF, Bokoch GM, Evans T, Snyderman R. rac, a novel ras-related family of proteins that are botulinum toxin substrates. J Biol Chem. 1989;264:16378–16382
  103. Shirsat NV, Pignolo RJ, Kreider BL, Rovera G. A member of the ras gene superfamily is expressed specifically in T, B and myeloid hemopoietic cells. Oncogene. 1990;5:769–772
  104. Movilla N, Dosil M, Zheng Y, Bustelo XR. How Vav proteins discriminate the GTPases Rac1 and RhoA from Cdc42. Oncogene. 2001;20:8057–8065
  105. Olson MF, Pasteris NG, Gorski JL, Hall A. Faciogenital dysplasia protein (FGD1) and Vav, two related proteins required for normal embryonic development, are upstream regulators of Rho GTPases. Curr Biol. 1996;6:1628–1633
  106. Scheffzek K, Stephan I, Jensen ON, Illenberger D, Gierschik P. The Rac-RhoGDI complex and the structural basis for the regulation of Rho proteins by RhoGDI. Nat Struct Biol. 2000;7:122–126
  107. Grizot S, Faure J, Fieschi F, Vignais PV, Dagher MC, Pebay-Peyroula E. Crystal structure of the Rac1-RhoGDI complex involved in nadph oxidase activation. Biochemistry. 2001;40:10007–10013
  108. Dib K, Melander F, Axelsson L, Dagher MC, Aspenstrom P, Andersson T. Down-regulation of Rac activity during β 2 integrin–mediated adhesion of human neutrophils. J Biol Chem. 2003;278:24181–24188
  109. Dong X, Mitchell DA, Lobo S, Zhao L, Bartels DJ, Deschenes RJ. Palmitoylation and plasma membrane localization of Ras2p by a nonclassical trafficking pathway in Saccharomyces cerevisiae. Mol Cell Biol. 2003;23:6574–6584
  110. Apolloni A, Prior IA, Lindsay M, Parton RG, Hancock JF. H-ras but not K-ras traffics to the plasma membrane through the exocytic pathway. Mol Cell Biol. 2000;20:2475–2487
  111. Roy MO, Leventis R, Silvius JR. Mutational and biochemical analysis of plasma membrane targeting mediated by the farnesylated, polybasic carboxy terminus of K-ras4B. Biochemistry. 2000;39:8298–8307
  112. Gelb MH, Scholten JD, Sebolt-Leopold JS. Protein prenylation: from discovery to prospects for cancer treatment. Curr Opin Chem Biol. 1998;2:40–48
  113. Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem. 1996;65:241–269
  114. Mira JP, Benard V, Groffen J, Sanders LC, Knaus UG. Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway. Proc Natl Acad Sci U S A. 2000;97:185–189
  115. Baugher PJ, Krishnamoorthy L, Price JE, Dharmawardhane SF. Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells. Breast Cancer Res. 2005;7:R965–R974
  116. Morris CM, Haataja L, McDonald M, et al. The small GTPase RAC3 gene is located within chromosome band 17q25.3 outside and telomeric of a region commonly deleted in breast and ovarian tumours. Cytogenet Cell Genet. 2000;89:18–23
  117. Keller PJ, Gable CM, Wing MR, Cox AD. Rac3-mediated transformation requires multiple effector pathways. Cancer Res. 2005;65:9883–9890
  118. Chan AY, Coniglio SJ, Chuang YY, et al. Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. Oncogene. 2005;24:7821–7829
  119. Cho YJ, Zhang B, Kaartinen V, et al. Generation of rac3 null mutant mice: role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia. Mol Cell Biol. 2005;25:5777–5785
  120. Corbetta S, Gualdoni S, Albertinazzi C, et al. Generation and characterization of Rac3 knockout mice. Mol Cell Biol. 2005;25:5763–5776
  121. Wang L, Yang L, Filippi MD, Williams DA, Zheng Y. Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment. Blood. 2006;107:98–105

PII: S0301-472X(06)00237-2

doi: 10.1016/j.exphem.2006.03.016

Experimental Hematology
Volume 34, Issue 8 , Pages 976-985 , August 2006