Intracellular Trafficking and Signaling: The Role of Endocytic Rab GTPase

  • M. Alejandro Barbieri
  • Marisa J. Wainszelbaum
  • Philip D. Stahl
Part of the Molecular Biology Intelligence Unit book series (MBIU)


Binding of growth factors and other cell-activating agents to cell surface receptors is known to trigger a complex series of events that initiate signal transduction. Ligand activation of many signal-transducing receptors accelerates receptor endocytosis. The classical view is that receptor internalization is primarily a mechanism of signal attenuation and receptor degradation, but more recent evidence suggests that internalization may mediate the formation of specialized signaling complexes on intracellular vesicles. The small Rab GTPases, master regulators of vesicle transport, can influence both receptor trafficking and receptor signaling pathways. They are localized to specific organelles and domains where they not only mediate vesicle docking and fusion but also influence the recruitment of effector proteins that mediate signal transduction and vesicle motility. It is interesting to speculate that extracellular stimuli contribute to the endocytosis of cell surface compo- nents for survival, defense, repair, storage and degradation. In addition, traffic regulation by external stimuli emphasizes the possible role in infection, aging, cancer and several degenerative diseases. Thus, receptor-mediated endocytosis regulation by small Rab GTPases not only provides a mechanism for attenuation of signaling but may also determine the quality of signal output by providing different combinations of downstream effectors at various endocytic compartments.


Epidermal Growth Factor Receptor Early Endosome Late Endosome Endosomal Membrane Receptor Trafficking 


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  1. 1.
    Segev N. Ypt and Rab GTPases: Insight into functions through novel interactions. Curr Opin Cell Biol 2001; 13:500–11.PubMedCrossRefGoogle Scholar
  2. 2.
    Segev N. Ypt/rab gtpases: Regulators of protein trafficking. Sci STKE 2001, (RE11). 3._Segev N. Cell biology: A TIP about Rabs. Science 2001; 292:1313–4.PubMedCrossRefGoogle Scholar
  3. 4.
    Novick P, Zerial M. The diversity of Rab proteins in vesicle transport. Curr Opin Cell Biol 1997; 9:496–504.PubMedCrossRefGoogle Scholar
  4. 5.
    McLauchlan H, Newell J, Morrice N et al. A novel role for Rab5-GDI in ligand sequestration into clathrin-coated pits. Curr Biol 1998; 8:34–45.PubMedCrossRefGoogle Scholar
  5. 6.
    Hammer Ilrd JA, Wu XS. Rabs grab motors: Defining the connections between Rab GTPases and motor proteins. Curr Opin Cell Biol 2002; 14:69–75.PubMedCrossRefGoogle Scholar
  6. 7.
    de Renzis S, Sonnichsen B, Zerial M. Divalent Rab effectors regulate the sub-compartmental organization and sorting of early endosomes. Nat Cell Biol 2002; 4:124–33.PubMedCrossRefGoogle Scholar
  7. 8.
    Christoforidis S, Zerial M. Purification and identification of novel Rab effectors using affinity chromatography. Methods 2000; 20:403–10.PubMedCrossRefGoogle Scholar
  8. 9.
    Horiuchi H, Lippe R, McBride HM et al. A novel Rab5 GDP/GTP exchange factor complexed to Rabaptin-5 links nucleotide exchange to effector recruitment and function. Cell 1997; 90:1149–59.PubMedCrossRefGoogle Scholar
  9. 10.
    Tall GG, Barbieri MA, Stahl PD et al. Ras-activated endocytosis is mediated by the Rab5 guanine nucleotide exchange activity of RIN1. Dev Cell 2001; 1:73–82.PubMedCrossRefGoogle Scholar
  10. 10a.
    Saito K, Murai J, Kajiho H et al. A novel binding protein composed of homophilic tetramer exhibits unique properties for the small GTPase Rab5. J Biol Chem 2002; 277:3412–8.PubMedCrossRefGoogle Scholar
  11. 10b.
    Kimura T, Sakisaka T, Baba T et al. Involvement of the Ras-Ras-activated Rab5 guanine nucleotide exchange factor RIN2-Rab5 pathway in the hepatocyte growth factor-induced endocytosis of E-cadherin. J Biol Chem 2006; 281:10598–609.PubMedCrossRefGoogle Scholar
  12. 10c.
    Kajiho H, Saito K, Tsujita K et al. RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway. J Cell Sci 2003; 116:4159–68.PubMedCrossRefGoogle Scholar
  13. l0d.
    Hadano S, Benn SC, Kakuta S et al. Mice deficient in the Rab5 guanine nucleotide exchange factor ALS2/alsin exhibit age-dependent neurological deficits and altered endosome trafficking. Hum Mol Genet 2006; 15:233–50.PubMedCrossRefGoogle Scholar
  14. l0e.
    Topp JD, Gray NW, Gerard RD, Horazdovsky BF. Alsin is a Rab5 and Racl guanine nucleotide exchange factor. J Biol Chem 2004; 279:24612–23PubMedCrossRefGoogle Scholar
  15. l0f.
    . Su X, Lodhi IJ, Saltiel AR, Stahl PD. Insulin-stimulated interaction between insulin receptor substrate 1 and p85alpha and activation of protein kinase B/Akt require Rab5. J Biol Chem 2006; 281:27982–90.PubMedCrossRefGoogle Scholar
  16. l0g.
    Hunker CM, Galvis A, Kruk I et al. Rab5-activating protein 6, a novel endosomal protein with a role in endocytosis. Biochem Biophys Res Commun 2006; 340:967–75.PubMedCrossRefGoogle Scholar
  17. 11.
    Sonnichsen B, De Renzis S, Nielsen E et al. Distinct membrane domains on endosomes in the recycling pathway visualized by multicolor imaging of Rab4, Rab5, and Rabll. J Cell Biol 2000; 149:901–14.PubMedCrossRefGoogle Scholar
  18. 12.
    Bucci C, Parton RG, Mather IH et al. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell 1992; 70:715–28.PubMedCrossRefGoogle Scholar
  19. 13.
    Gorvel JP, Chavrier P, Zerial M et al. rab5 controls early endosome fusion in vitro. Cell 1991; 64:915–25.PubMedCrossRefGoogle Scholar
  20. 14.
    Li G, Barbieri MA, Colombo MI et al. Structural features of the GTP-binding defective Rab5 mutants required for their inhibitory activity on endocytosis. J Biol Chem 1994; 269:14631–5.PubMedGoogle Scholar
  21. 15.
    Li G, Stahl PD. Structure-function relationship of the small GTPase rab5. J Biol Chem 1993; 268:24475–80.PubMedGoogle Scholar
  22. 16.
    Stenmark H, Parton RG, Steele-Mortimer O et al. Inhibition of rab5 GTPase activity stimulates membrane fusion in endocytosis. EMBO J 1994; 13:1287–96.PubMedGoogle Scholar
  23. 17.
    Barbieri MA, Hoffenberg S, Roberts R et al. Evidence for a symmetrical requirement for Rab5-GTP in in vitro endosome-endosome fusion. J Biol Chem 1998; 273:25850–5.PubMedCrossRefGoogle Scholar
  24. 18.
    Rubino M, Miaczynska M, Lippe R et al. Selective membrane recruitment of EEA1 suggests a role in directional transport of clathrin-coated vesicles to early endosomes. J Biol Chem 2000; 275:3745–8.PubMedCrossRefGoogle Scholar
  25. 19.
    Barbieri MA, Roberts RL, Gumusboga A et al. Epidermal growth factor and membrane trafficking. EGF receptor activation of endocytosis requires Rab5a. J Cell Biol 2000; 151:539–50.PubMedCrossRefGoogle Scholar
  26. 20.
    Roberts RL, Barbieri MA, Pryse KM et al. Endosome fusion in living cells overexpressing GFP-rab5. J Cell Sci 1999; 112(Pt 21):3667–75.PubMedGoogle Scholar
  27. 21.
    Van Der Sluijs P, Hull M, Zahraoui A et al. The small GTP-binding protein rab4 is associated with early endosomes. Proc Natl Acad Sci USA 1991; 88:6313–7.CrossRefGoogle Scholar
  28. 22.
    Bottger G, Nagelkerken B, van der Sluijs P. Rab4 and Rab7 define distinct nonoverlapping endosomal compartments. J Biol Chem 1996; 271:29191–7.PubMedCrossRefGoogle Scholar
  29. 23.
    van der Sluijs P, Hull M, Webster P et al. The small GTP-binding protein rab4 controls an early sorting event on the endocytic pathway. Cell 1992; 70:729–40.PubMedCrossRefGoogle Scholar
  30. 24.
    Bailly E, McCaffrey M, Touchot N et al. Phosphorylation of two small GTP-binding proteins of the Rab family by p34cdc2. Nature 1991; 350:715–8.PubMedCrossRefGoogle Scholar
  31. 25.
    van der Sluijs P, Hull M, Huber LA et al. Reversible phosphorylation—dephosphorylation determines the localization of rab4 during the cell cycle. EMBO J 1992; 11:4379–89.PubMedGoogle Scholar
  32. 26.
    Nagelkerken B, Van Anken E, Van Raak M et al. Rabaptin4, a novel effector of the small GTPase rab4a, is recruited to perinuclear recycling vesicles. Biochem J 2000; 346(Pt 3):593–601.PubMedCrossRefGoogle Scholar
  33. 27.
    Ullrich O, Reinsch S, Urbe S et al. Rabll regulates recycling through the pericentriolar recycling endosome. J Cell Biol 1996; 135:913–24.PubMedCrossRefGoogle Scholar
  34. 28.
    Ren M, Xu G, Zeng J et al. Hydrolysis of GTP on rabll is required for the direct delivery of transferrin from the pericentriolar recycling compartment to the cell surface but not from sorting endosomes. Proc Natl Acad Sci USA 1998; 95:6187–92.PubMedCrossRefGoogle Scholar
  35. 29.
    Wallace DM, Lindsay AJ, Hendrick AG et al. Rabll-FIP4 interacts with Rabll in a GTP-dependent manner and its overexpression condenses the Rabll positive compartment in HeLa cells. Biochem Biophys Res Commun 2002; 299:770–9.PubMedCrossRefGoogle Scholar
  36. 30.
    Kornfeld S, Mellman I. The biogenesis of lysosomes. Annu Rev Cell Biol 1989; 5:483–525.PubMedCrossRefGoogle Scholar
  37. 31.
    Feng Y, Press B, Wandinger-Ness A. Rab 7: An important regulator of late endocytic membrane traffic. J Cell Biol 1995; 131:1435–52.PubMedCrossRefGoogle Scholar
  38. 32.
    Press B, Feng Y, Hoflack B et al. Mutant Rab7 causes the accumulation of cathepsin D and cation-independent mannose 6-phosphate receptor in an early endocytic compartment. J Cell Biol 1998; 140:1075–89.PubMedCrossRefGoogle Scholar
  39. 33.
    Jordens I, Fernandez-Borja M, Marsman M et al. The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors. Curr Biol 2001; 11:1680–5.PubMedCrossRefGoogle Scholar
  40. 34.
    Rieder SE, Emr SD. A novel RING finger protein complex essential for a late step in protein transport to the yeast vacuole. Mol Biol Cell 1997; 8:2307–27.PubMedGoogle Scholar
  41. 35.
    Price A, Seals D, Wickner W et al. The docking stage of yeast vacuole fusion requires the transfer of proteins from a cis-SNARE complex to a Rab/Ypt protein. J Cell Biol 2000; 148:1231–8.PubMedCrossRefGoogle Scholar
  42. 36.
    Seals DF, Eitzen G, Margolis N et al. A Ypt/Rab effector complex containing the Seel homolog Vps33p is required for homotypic vacuole fusion. Proc Natl Acad Sci USA 2000; 97:9402–7.PubMedCrossRefGoogle Scholar
  43. 37.
    Lombardi D, Soldati T, Riederer MA et al. Rab9 functions in transport between late endosomes and the trans Golgi network. EMBO J 1993; 12:677–82.PubMedGoogle Scholar
  44. 38.
    Diaz E, Schimmoller F, Pfeffer SR. A novel Rab9 effector required for endosome-to-TGN transport. J Cell Biol 1997; 138:283–90.PubMedCrossRefGoogle Scholar
  45. 39.
    Riederer MA, Soldati T, Shapiro AD et al. Lysosome biogenesis requires Rab9 function and receptor recycling from endosomes to the trans-Golgi network. J Cell Biol 1994; 125:573–82.PubMedCrossRefGoogle Scholar
  46. 40.
    Rink J, Ghigo E, Kalaidzidis Y et al. Rab conversion as a mechanism of progression from early to late endosomes. Cell 2005; 122:735–49.PubMedCrossRefGoogle Scholar
  47. 40a.
    Rink J, Ghigo E, Kalaidzidis Y, Zerial M. Rab conversion as a mechanism of progression from early to late endosomes. Cell 2005; 122:735–49.PubMedCrossRefGoogle Scholar
  48. 41.
    Lutcke A, Jansson S, Parton RG et al. Rab 17, a novel small GTPase, is specific for epithelial cells and is induced during cell polarization. J Cell Biol 1993; 121:553–64.PubMedCrossRefGoogle Scholar
  49. 42.
    Zacchi P, Stenmark H, Parton RG et al. Rab 17 regulates membrane trafficking through apical recycling endosomes in polarized epithelial cells. J Cell Biol 1998; 140:1039–53.PubMedCrossRefGoogle Scholar
  50. 43.
    Hunziker W, Peters PJ. Rab 17 localizes to recycling endosomes and regulates receptor-mediated transcytosis in epithelial cells. J Biol Chem 1998; 273:15734–41.PubMedCrossRefGoogle Scholar
  51. 44.
    Olkkonen VM, Dupree P, Killisch I et al. Molecular cloning and subcellular localization of three GTP-binding proteins of the rab subfamily. J Cell Sci 1993; 106(Pt 4):1249–61.PubMedGoogle Scholar
  52. 45.
    Mesa R, Salomon C, Roggero M et al. Rab22a affects the morphology and function of the endocytic pathway. J Cell Sci 2001; 114:4041–9.PubMedGoogle Scholar
  53. 46.
    Kauppi M, Simonsen A, Bremnes B et al. The small GTPase Rab22 interacts with EEA1 and controls endosomal membrane trafficking. J Cell Sci 2002; 115:899–911.PubMedGoogle Scholar
  54. 46a.
    Magadan JG, Barbieri MA, Mesa R et al. Rab22a regulates the sorting of transferrin to recycling endosomes. Mol Cell Biol 2006; 26:2595–61.PubMedCrossRefGoogle Scholar
  55. 47.
    Geuze HJ, Slot JW, Strous GJ et al. The pathway of the asialoglycoprotein-ligand during receptor-mediated endocytosis: A morphological study with colloidal gold/ligand in the human hepatoma cell line, Hep G2. Eur J Cell Biol 1983; 32:38–44.PubMedGoogle Scholar
  56. 48.
    Griffiths G, Back R, Marsh M. A quantitative analysis of the endocytic pathway in baby hamster kidney cells. J Cell Biol 1989; 109:2703–20.PubMedCrossRefGoogle Scholar
  57. 49.
    Galli T, McPherson PS, De Camilli P. The V0 sector of the V-ATPase, synaptobrevin, and synaptophysin are associated on synaptic vesicles in a Triton X-100-resistant, freeze-thawing sensitive, complex. J Biol Chem 1996; 271:2193–8.PubMedCrossRefGoogle Scholar
  58. 50.
    Steegmaier M, Lee KC, Prekeris R et al. SNARE protein trafficking in polarized MDCK cells. Traffic 2000; 1:553–60.PubMedCrossRefGoogle Scholar
  59. 51.
    Prekeris R, Klumperman J, Chen YA et al. Syntaxin 13 mediates cycling of plasma membrane proteins via tubulovesicular recycling endosomes. J Cell Biol 1998; 143:957–71.PubMedCrossRefGoogle Scholar
  60. 52.
    McBride HM, Rybin V, Murphy C et al. Oligomeric complexes link Rab5 effectors with NSF and drive membrane fusion via interactions between EEA1 and syntaxin 13. Cell 1999; 98:377–86.PubMedCrossRefGoogle Scholar
  61. 53.
    Haigler HT, McKanna JA, Cohen S. Rapid stimulation of pinocytosis in human carcinoma cells A-431 by epidermal growth factor. J Cell Biol 1979; 83:82–90.PubMedCrossRefGoogle Scholar
  62. 54.
    Wiley HS, Cunningham DD. Epidermal growth factor stimulates fluid phase endocytosis in human fibroblasts through a signal generated at the cell surface. J Cell Biochem 1982; 19:383–94.PubMedCrossRefGoogle Scholar
  63. 55.
    Wiley HS, Kaplan J. Epidermal growth factor rapidly induces a redistribution of transferrin receptor pools in human fibroblasts. Proc Natl Acad Sci USA 1984; 81:7456–60.PubMedCrossRefGoogle Scholar
  64. 56.
    Bretscher MS, Aguado-Velasco C. EGF induces recycling membrane to form ruffles. Curr Biol 1998; 8:721–4.PubMedCrossRefGoogle Scholar
  65. 57.
    Wiley HS. Anomalous binding of epidermal growth factor to A431 cells is due to the effect of high receptor densities and a saturable endocytic system. J Cell Biol 1988; 107:801–10.PubMedCrossRefGoogle Scholar
  66. 58.
    West MA, Bretscher MS, Watts C. Distinct endocytotic pathways in epidermal growth factor-stimulated human carcinoma A431 cells. J Cell Biol 1989; 109:2731–9.PubMedCrossRefGoogle Scholar
  67. 59.
    Wiley HS, VanNostrand W, McKinley DN et al. Intracellular processing of epidermal growth factor and its effect on ligand-receptor interactions. J Biol Chem 1985; 260:5290–5.PubMedGoogle Scholar
  68. 60.
    Di Guglielmo GM, Baass PC, Ou WJ et al. Compartmentalization of SHC, GRB2 and mSOS, and hyperphosphorylation of Raf-1 by EGF but not insulin in liver parenchyma. EMBO J 1994; 13:4269–77.PubMedGoogle Scholar
  69. 61.
    van der Geer P, Hunter T, Lindberg RA. Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol 1994; 10:251–337.PubMedCrossRefGoogle Scholar
  70. 62.
    Adamson P, Paterson HF, Hall A. Intracellular localization of the P21rho proteins. J Cell Biol 1992; 119:617–27.PubMedCrossRefGoogle Scholar
  71. 63.
    Kaplan KB, Swedlow JR, Varmus HE et al. Association of p60c-src with endosomal membranes in mammalian fibroblasts. J Cell Biol 1992; 118:321–33.PubMedCrossRefGoogle Scholar
  72. 64.
    Vieira AV, Lamaze C, Schmid SL. Control of EGF receptor signaling by clathrin-mediated endocytosis. Science 1996; 274:2086–9.PubMedCrossRefGoogle Scholar
  73. 65.
    Ahn S, Maudsley S, Luttrell LM et al. Src-mediated tyrosine phosphorylation of dynamin is required for beta2-adrenergic receptor internalization and mitogen-activated protein kinase signaling. J Biol Chem 1999; 274:1185–8.PubMedCrossRefGoogle Scholar
  74. 66.
    Daaka Y, Luttrell LM, Ahn S et al. Essential role for G protein-coupled receptor endocytosis in the activation of mitogen-activated protein kinase. J Biol Chem 1998; 273:685–8.PubMedCrossRefGoogle Scholar
  75. 67.
    Luttrell LM, Ferguson SS, Daaka Y et al. Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science 1999; 283:655–61.PubMedCrossRefGoogle Scholar
  76. 68.
    Laporte SA, Oakley RH, Zhang J et al. The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis. Proc Natl Acad Sci USA 1999; 96:3712–7.PubMedCrossRefGoogle Scholar
  77. 69.
    Ferguson SS. Evolving concepts in G protein-coupled receptor endocytosis: The role in receptor desensitization and signaling. Pharmacol Rev 2001; 53:1–24.PubMedGoogle Scholar
  78. 70.
    McDonald PH, Lefkowitz RJ. Beta-Arrestins: New roles in regulating heptahelical receptors’ functions. Cell Signal 2001; 13:683–9.PubMedCrossRefGoogle Scholar
  79. 71.
    Laporte SA, Miller WE, Kim KM et al. beta-Arrestin/AP-2 interaction in G protein-coupled receptor internalization: Identification of a beta-arrestin binging site in beta 2-adaptin. J Biol Chem 2002; 277:9247–54.PubMedCrossRefGoogle Scholar
  80. 72.
    Luttrell LM, Lefkowitz RJ. The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci 2002; 115:455–65.PubMedGoogle Scholar
  81. 73.
    McPherson PS, Kay BK, Hussain NK. Signaling on the endocytic pathway. Traffic 2001; 2:375–84.PubMedCrossRefGoogle Scholar
  82. 74.
    Luttrell LM, Delia Rocca GJ, van Biesen T et al. Gbetagamma subunits mediate Src-dependent phosphorylation of the epidermal growth factor receptor. A scaffold for G protein-coupled receptor-mediated Ras activation. J Biol Chem 1997; 272:4637–44.PubMedCrossRefGoogle Scholar
  83. 75.
    Hackel PO, Zwick E, Prenzel N et al. Epidermal growth factor receptors: Critical mediators of multiple receptor pathways. Curr Opin Cell Biol 1999; 11:184–9.PubMedCrossRefGoogle Scholar
  84. 76.
    Daub H, Weiss FU, Wallasch C et al. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 1996; 379:557–60.PubMedCrossRefGoogle Scholar
  85. 77.
    Daub H, Wallasch C, Lankenau A et al. Signal characteristics of G protein-transactivated EGF receptor. EMBO J 1997; 16:7032–44.PubMedCrossRefGoogle Scholar
  86. 78.
    Zwick E, Wallasch C, Daub H et al. Distinct calcium-dependent pathways of epidermal growth factor receptor transactivation and PYK2 tyrosine phosphorylation in PC 12 cells. J Biol Chem 1999; 274:20989–96.PubMedCrossRefGoogle Scholar
  87. 79.
    Lee FS, Chao MV. Activation of Trk neurotrophin receptors in the absence of neurotrophins. Proc Natl Acad Sci USA 2001; 98:3555–60.PubMedCrossRefGoogle Scholar
  88. 80.
    Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev 1998; 50:413–92.PubMedGoogle Scholar
  89. 81.
    Berg MM, Sternberg DW, Parada LF et al. K-252a inhibits nerve growth factor-induced trk proto-oncogene tyrosine phosphorylation and kinase activity. J Biol Chem 1992; 267:13–6.PubMedGoogle Scholar
  90. 82.
    Zwick E, Hackel PO, Prenzel N et al. The EGF receptor as central transducer of heterologous signalling systems. Trends Pharmacol Sci 1999; 20:408–12.PubMedCrossRefGoogle Scholar
  91. 83.
    Eguchi S, Numaguchi K, Iwasaki H et al. Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin Il-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. J Biol Chem 1998; 273:8890–6.PubMedCrossRefGoogle Scholar
  92. 84.
    Gao Z, Chen T, Weber MJ et al. A2B adenosine and P2Y2 receptors stimulate mitogen-activated protein kinase in human embryonic kidney-293 cells, cross-talk between cyclic AMP and protein kinase c pathways. J Biol Chem 1999; 274:5972–80.PubMedCrossRefGoogle Scholar
  93. 85.
    Seidel MG, Klinger M, Freissmuth M et al. Activation of mitogen-activated protein kinase by the A(2A)-adenosine receptor via a rap 1-dependent and via a p21(ras)-dependent pathway. J Biol Chem 1999; 274:25833–41.PubMedCrossRefGoogle Scholar
  94. 86.
    Sexl V, Mancusi G, Holler C et al. Stimulation of the mitogen-activated protein kinase via the A2A-adenosine receptor in primary human endothelial cells. J Biol Chem 1997; 272:5792–9.PubMedCrossRefGoogle Scholar
  95. 87.
    Han L, Colicelli J. A human protein selected for interference with Ras function interacts directly with Ras and competes with Rafl. Mol Cell Biol 1995; 15:1318–23.PubMedGoogle Scholar
  96. 88.
    Barbieri MA, Kong C, Chen PI et al. The SRC homology 2 domain of Rinl mediates its binding to the epidermal growth factor receptor and regulates receptor endocytosis. J Biol Chem 2003; 278:32027–36.PubMedCrossRefGoogle Scholar
  97. 89.
    Lim YM, Wong S, Lau G et al. BCR/ABL inhibition by an escort/phosphatase fusion protein. Proc Natl Acad Sci USA 2000; 97:12233–8.PubMedCrossRefGoogle Scholar
  98. 90.
    Afar DE, Han L, McLaughlin J et al. Regulation of the oncogenic activity of BCR-ABL by a tightly bound substrate protein RINl. Immunity 1997; 6:773–82.PubMedCrossRefGoogle Scholar
  99. 91.
    Han L, Wong D, Dhaka A et al. Protein binding and signaling properties of RINl suggest a unique effector function. Proc Natl Acad Sci USA 1997; 94:4954–9.PubMedCrossRefGoogle Scholar
  100. 92.
    Wells A, Welsh JB, Lazar CS et al. Ligand-induced transformation by a noninternalizing epidermal growth factor receptor. Science 1990; 247:962–4.PubMedCrossRefGoogle Scholar
  101. 93.
    Bar-Sagi D, Feramisco JR. Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins. Science 1986; 233:1061–8.PubMedCrossRefGoogle Scholar
  102. 94.
    Cavalli V, Vilbois F, Corti M et al. The stress-induced MAP kinase p38 regulates endocytic trafficking via the GDI:Rab5 complex. Mol Cell 2001; 7:421–32.PubMedCrossRefGoogle Scholar
  103. 95.
    Di Fiore PP, Gill GN. Endocytosis and mitogenic signaling. Curr Opin Cell Biol 1999; 11:483–8.PubMedCrossRefGoogle Scholar
  104. 96.
    Levkowitz G, Waterman H, Zamir E et al. c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Genes Dev 1998; 12:3663–74.PubMedCrossRefGoogle Scholar
  105. 97.
    Haugh JM, Huang AC, Wiley HS et al. Internalized epidermal growth factor receptors participate in the activation of p21(ras) in fibroblasts. J Biol Chem 1999; 274:34350–60.PubMedCrossRefGoogle Scholar
  106. 98.
    Haugh JM, Meyer T. Active EGF receptors have limited access to PtdIns(4,5)P(2) in endosomes: Implications for phospholipase C and PI 3-kinase signaling. J Cell Sci 2002; 115:303–10.PubMedGoogle Scholar
  107. 99.
    Chang CP, Kao JP, Lazar CS et al. Ligand-induced internalization and increased cell calcium are mediated via distinct structural elements in the carboxyl terminus of the epidermal growth factor receptor. J Biol Chem 1991; 266:23467–70.PubMedGoogle Scholar
  108. 100.
    Sorkin A, Von Zastrow M. Signal transduction and endocytosis: Close encounters of many kinds. Nat Rev Mol Cell Biol 2002; 3:600–14.PubMedCrossRefGoogle Scholar
  109. 101.
    Herbst JJ, Opresko LK, Walsh BJ et al. Regulation of postendocytic trafficking of the epidermal growth factor receptor through endosomal retention. J Biol Chem 1994; 269:12865–73.PubMedGoogle Scholar
  110. 102.
    Levkowitz G, Waterman H, Ettenberg SA et al. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol Cell 1999; 4:1029–40.PubMedCrossRefGoogle Scholar
  111. 103.
    Yokouchi M, Kondo T, Houghton A et al. Ligand-induced ubiquitination of the epidermal growth factor receptor involves the interaction of the c-Cbl RING finger and UbcH7. J Biol Chem 1999; 274:31707–12.PubMedCrossRefGoogle Scholar
  112. 104.
    Jongeward GD, Clandinin TR, Sternberg PW. sli-1, a negative regulator of let-23-mediated signaling in C. elegans. Genetics 1995; 139:1553–66.PubMedGoogle Scholar
  113. 105.
    Miyake S, Mullane-Robinson KP, Lill NL et al. Cbl-mediated negative regulation of platelet-derived growth factor receptor-dependent cell proliferation. A critical role for Cbl tyrosine kinase-binding domain. J Biol Chem 1999; 274:16619–28.PubMedCrossRefGoogle Scholar
  114. 106.
    Lee PS, Wang Y, Dominguez MG et al. The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation. EMBO J 1999; 18:3616–28.PubMedCrossRefGoogle Scholar
  115. 107.
    French AR, Sudlow GP, Wiley HS et al. Postendocytic trafficking of epidermal growth factor-receptor complexes is mediated through saturable and specific endosomal interactions. J Biol Chem 1994; 269:15749–55.PubMedGoogle Scholar
  116. 108.
    Wiley HS, Herbst JJ, Walsh BJ et al. The role of tyrosine kinase activity in endocytosis, compartmentation, and down-regulation of the epidermal growth factor receptor. J Biol Chem 1991; 266:11083–94.PubMedGoogle Scholar
  117. 109.
    Murphy MA, Schnall RG, Venter DJ et al. Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice. Mol Cell Biol 1998; 18:4872–82.PubMedGoogle Scholar
  118. 110.
    Waterman H, Sabanai I, Geiger B et al. Alternative intracellular routing of ErbB receptors may determine signaling potency. J Biol Chem 1998; 273:13819–27.PubMedCrossRefGoogle Scholar
  119. 111.
    Katzmann DJ, Babst M, Emr SD. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell 2001; 106:145–55.PubMedCrossRefGoogle Scholar
  120. 112.
    Katzmann DJ, Stefan CJ, Babst M et al. Vps27 recruits ESCRT machinery to endosomes during MVB sorting. J Cell Biol 2003; 162:413–23.PubMedCrossRefGoogle Scholar
  121. 113.
    Wong ES, Fong CW, Lim J et al. Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequendy enhances Ras/ERK signalling. EMBO J 2002; 21:4796–808.PubMedCrossRefGoogle Scholar
  122. 114.
    Soubeyran P, Kowanetz K, Szymkiewicz I et al. Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature 2002; 416:183–7.PubMedCrossRefGoogle Scholar
  123. 115.
    Glenney Jr JR, Chen WS, Lazar CS et al. Ligand-induced endocytosis of the EGF receptor is blocked by mutational inactivation and by microinjection of anti-phosphotyrosine antibodies. Cell 1988; 52:675–84.PubMedCrossRefGoogle Scholar
  124. 116.
    Gorvel JP, Moreno E. Brucella intracellular life: From invasion to intracellular replication. Vet Microbiol 2002; 90, 281–97.PubMedCrossRefGoogle Scholar
  125. 117.
    Vieira OV, Botelho RJ, Grinstein S. Phagosome maturation: Aging gracefully. Biochem J 2002; 366:689–704.PubMedGoogle Scholar
  126. 118.
    Pei L, Peng Y, Yang Y et al. PRC 17, a novel oncogene encoding a Rab GTPase-activating protein, is amplified in prostate cancer. Cancer Res 2002; 62:5420–4.PubMedGoogle Scholar
  127. 118a.
    Wainszelbaum MJ, Charron AJ, Kong C et al. The hominoid-specific oncogene TBC1D3 activates Ras and modulates epidermal growth factor receptor signaling and trafficking. J Biol Chem 2008; 283:13233–42PubMedCrossRefGoogle Scholar
  128. 119.
    Magnusson MK, Meade KE, Brown KE et al. Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia. Blood 2001; 98:2518–25.PubMedCrossRefGoogle Scholar
  129. 120.
    Liu FL, Li Y, Gao LH et al. Studies of the cellular biological function of expression change of RAB5A gene in human lung adenocarcinoma GLC-82 and SPC-al. Yi Chuan Xue Bao 2002; 29:1043–7.PubMedGoogle Scholar
  130. 121.
    Li Y, Meng X, Feng H et al. Over-expression of the RAB5 gene in human lung adenocarcinoma cells with high metastatic potential. Chin Med Sci J 1999; 14:96–101.PubMedGoogle Scholar
  131. 122.
    Barral DC, Ramalho JS, Anders R et al. Functional redundancy of Rab27 proteins and the pathogenesis of Griscelli syndrome. J Clin Invest 2002; 110:247–57.PubMedGoogle Scholar
  132. 123.
    Seabra MC, Mules EH, Hume AN. Rab GTPases, intracellular traffic and disease. Trends Mol Med 2002; 8:23–30.PubMedCrossRefGoogle Scholar
  133. 124.
    Kawasaki M, Nakayama K, Wakatsuki S. Membrane recruitment of effector proteins by Arf and Rab GTPases. Curr Opin Struct Biol 2005; 15:681–9.PubMedCrossRefGoogle Scholar
  134. 125.
    Vitale G, Rybin V, Christoforidis S et al. Distinct Rab-binding domains mediate the interaction of Rabaptin-5 with GTP-bound Rab4 and Rab5. EMBO J 1998; 17:1941–51.PubMedCrossRefGoogle Scholar
  135. 126.
    Lindsay AJ, Hendrick AG, Cantalupo G et al. Rab coupling protein (RCP), a novel Rab4 and Rabll effector protein. J Biol Chem 2002; 277:12190–9.PubMedCrossRefGoogle Scholar
  136. 127.
    Hickson GR, Matheson J, Riggs B et al. Arfophilins are dual Arf/Rab 11 binding proteins that regulate recycling endosome distribution and are related to Drosophila nuclear fallout. Mol Biol Cell 2003; 14:2908–20.PubMedCrossRefGoogle Scholar
  137. 127a.
    Mattera R, Arighi CN, Lodge R et al. Divalent interaction of the GGAs with the Rabaptin-5-Rabex-5 complex. EMBO J 2003; 22(l):78–88.PubMedCrossRefGoogle Scholar
  138. 127b.
    Jacques KM, Nie Z, Stauffer S et al. Arfl dissociates from the clathrin adaptor GGA prior to being inactivated by Arf GTPase-activating proteins. J Biol Chem 2002; 277(49):47235–41.PubMedCrossRefGoogle Scholar
  139. 128.
    Balana ME, Niedergang F, Subtil A et al. ARF6 GTPase controls bacterial invasion by actin remodelling. J Cell Sci 2005; 118:2201–10.PubMedCrossRefGoogle Scholar
  140. 129.
    Amor JC, Swails J, Zhu X et al. The structure of RalF, an ADP-ribosylation factor guanine nucleotide exchange factor from Legionella pneumophila, reveals the presence of a cap over the active site. J Biol Chem 2005; 280:1392–400.PubMedCrossRefGoogle Scholar
  141. 130.
    Faure J, Stalder R, Borel C et al. ARF1 regulates Nef-induced CD4 degradation. Curr Biol 2004; 14:1056–64.PubMedCrossRefGoogle Scholar
  142. 131.
    Belov GA, Fogg MH, Ehrenfeld E. Poliovirus proteins induce membrane association of GTPase ADP-ribosylation factor. J Virol 2005; 79:7207–16.PubMedCrossRefGoogle Scholar
  143. 132.
    Hashimoto S, Onodera Y, Hashimoto A et al. Requirement for Arf6 in breast cancer invasive activities. Proc Natl Acad Sci USA 2004; 101:6647–52.PubMedCrossRefGoogle Scholar
  144. 133.
    Tague SE, Muralidharan V, D’Souza-Schorey C. ADP-ribosylation factor 6 regulates tumor cell invasion through the activation of the MEK/ERK signaling pathway. Proc Natl Acad Sci USA 2004; 101:9671–6.PubMedCrossRefGoogle Scholar
  145. 134.
    Ikeda S, Ushio-Fukai M, Zuo L et al. Novel role of ARF6 in vascular endothelial growth factor-induced signaling and angiogenesis. Circ Res 2005; 96:467–75.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • M. Alejandro Barbieri
    • 2
  • Marisa J. Wainszelbaum
    • 1
  • Philip D. Stahl
    • 1
  1. 1.Department of Cell Biology and PhysiologyWashington University School of MedicineSt. LouisUSA
  2. 2.Department of Biological SciencesFlorida International UniversityMiamiUSA

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