Protein & Cell

, Volume 2, Issue 1, pp 13–25 | Cite as

Small GTPases and cilia

  • Yujie Li
  • Jinghua HuEmail author


Small GTPases are key molecular switches that bind and hydrolyze GTP in diverse membrane- and cytoskeleton-related cellular processes. Recently, mounting evidences have highlighted the role of various small GTPases, including the members in Arf/Arl, Rab, and Ran subfamilies, in cilia formation and function. Once overlooked as an evolutionary vestige, the primary cilium has attracted more and more attention in last decade because of its role in sensing various extracellular signals and the association between cilia dysfunction and a wide spectrum of human diseases, now called ciliopathies. Here we review recent advances about the function of small GTPases in the context of cilia, and the correlation between the functional impairment of small GTPases and ciliopathies. Understanding of these cellular processes is of fundamental importance for broadening our view of cilia development and function in normal and pathological states and for providing valuable insights into the role of various small GTPases in disease processes, and their potential as therapeutic targets.


Small GTPase cilia ciliopathy 


  1. Ansley, S.J., Badano, J.L., Blacque, O.E., Hill, J., Hoskins, B.E., Leitch, C.C., Kim, J.C., Ross, A.J., Eichers, E.R., Teslovich, T.M., et al. (2003). Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425, 628–633.PubMedGoogle Scholar
  2. Avidor-Reiss, T., Maer, A.M., Koundakjian, E., Polyanovsky, A., Keil, T., Subramaniam, S., and Zuker, C.S. (2004). Decoding cilia function: defining specialized genes required for compartmentalized cilia biogenesis. Cell 117, 527–539.PubMedGoogle Scholar
  3. Babbey, C.M., Bacallao, R.L., and Dunn, K.W. (2010). Rab10 associates with primary cilia and the exocyst complex in renal epithelial cells. Am J Physiol Renal Physiol 299, F495–F506.PubMedGoogle Scholar
  4. Badano, J.L., Mitsuma, N., Beales, P.L., and Katsanis, N. (2006). The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7, 125–148.PubMedGoogle Scholar
  5. Bae, Y.K., Lyman-Gingerich, J., Barr, M.M., and Knobel, K.M. (2008). Identification of genes involved in the ciliary trafficking of C. elegans PKD-2. Dev Dyn 237, 2021–2029.PubMedGoogle Scholar
  6. Bae, Y.K., Qin, H., Knobel, K.M., Hu, J., Rosenbaum, J.L., and Barr, M.M. (2006). General and cell-type specific mechanisms target TRPP2/PKD-2 to cilia. Development 133, 3859–3870.PubMedGoogle Scholar
  7. Barr, M.M. (2005). Caenorhabditis elegans as a model to study renal development and disease: sexy cilia. J Am Soc Nephrol 16, 305–312.PubMedGoogle Scholar
  8. Barr, M.M., DeModena, J., Braun, D., Nguyen, C.Q., Hall, D.H., and Sternberg, P.W. (2001). The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway. Curr Biol 11, 1341–1346.PubMedGoogle Scholar
  9. Barr, M.M., and Sternberg, P.W. (1999). A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans. Nature 401, 386–389.PubMedGoogle Scholar
  10. Berbari, N.F., Lewis, J.S., Bishop, G.A., Askwith, C.C., and Mykytyn, K. (2008). Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci U S A 105, 4242–4246.PubMedGoogle Scholar
  11. Bernards, A., and Settleman, J. (2004). GAP control: regulating the regulators of small GTPases. Trends Cell Biol 14, 377–385.PubMedGoogle Scholar
  12. Bialas, N.J., Inglis, P.N., Li, C., Robinson, J.F., Parker, J.D., Healey, M.P., Davis, E.E., Inglis, C.D., Toivonen, T., Cottell, D.C.,et al. (2009). Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins. J Cell Sci 122, 611–624.PubMedGoogle Scholar
  13. Blacque, O.E., Perens, E.A., Boroevich, K.A., Inglis, P.N., Li, C., Warner, A., Khattra, J., Holt, R.A., Ou, G., Mah, A.K.,et al. (2005). Functional genomics of the cilium, a sensory organelle. Curr Biol 15, 935–941.PubMedGoogle Scholar
  14. Blacque, O.E., Reardon, M.J., Li, C., McCarthy, J., Mahjoub, M.R., Ansley, S.J., Badano, J.L., Mah, A.K., Beales, P.L., Davidson, W. S., et al. (2004). Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev 18, 1630–1642.PubMedGoogle Scholar
  15. Boehlke, C., Bashkurov, M., Buescher, A., Krick, T., John, A.K., Nitschke, R., Walz, G., and Kuehn, E.W. (2010). Differential role of Rab proteins in ciliary trafficking: Rab23 regulates smoothened levels. J Cell Sci 123, 1460–1467.PubMedGoogle Scholar
  16. Boguski, M.S., and McCormick, F. (1993). Proteins regulating Ras and its relatives. Nature 366, 643–654.PubMedGoogle Scholar
  17. Caspary, T., Larkins, C.E., and Anderson, K.V. (2007). The graded response to Sonic Hedgehog depends on cilia architecture. Dev Cell 12, 767–778.PubMedGoogle Scholar
  18. Cevik, S., Hori, Y., Kaplan, O.I., Kida, K., Toivenon, T., Foley-Fisher, C., Cottell, D., Katada, T., Kontani, K., and Blacque, O.E. (2010). Joubert syndrome Arl13b functions at ciliary membranes and stabilizes protein transport in Caenorhabditis elegans. J Cell Biol 188, 953–969.PubMedGoogle Scholar
  19. Chen, N., Mah, A., Blacque, O.E., Chu, J., Phgora, K., Bakhoum, M. W., Newbury, C.R., Khattra, J., Chan, S., Go, A.,et al. (2006). Identification of ciliary and ciliopathy genes in Caenorhabditis elegans through comparative genomics. Genome Biol 7, R126.PubMedGoogle Scholar
  20. Cherfils, J., and Chardin, P. (1999). GEFs: structural basis for their activation of small GTP-binding proteins. Trends Biochem Sci 24, 306–311.PubMedGoogle Scholar
  21. Chiang, A.P., Nishimura, D., Searby, C., Elbedour, K., Carmi, R., Ferguson, A.L., Secrist, J., Braun, T., Casavant, T., Stone, E.M., et al. (2004). Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3). Am J Hum Genet 75, 475–484.PubMedGoogle Scholar
  22. Clarke, P.R., and Zhang, C. (2008). Spatial and temporal coordination of mitosis by Ran GTPase. Nat Rev Mol Cell Biol 9, 464–477.PubMedGoogle Scholar
  23. Cuvillier, A., Redon, F., Antoine, J.C., Chardin, P., DeVos, T., and Merlin, G. (2000). LdARL-3A, a Leishmania promastigote-specific ADP-ribosylation factor-like protein, is essential for flagellum integrity. J Cell Sci 113, 2065–2074.PubMedGoogle Scholar
  24. D’souza-Schorey, C., and Chavrier, P. (2006). ARF proteins: roles in membrane traffic and beyond. Nat Rev Mol Cell Biol 7, 347–358.PubMedGoogle Scholar
  25. de Renzis, S., Sönnichsen, B., and Zerial, M. (2002). Divalent Rab effectors regulate the sub-compartmental organization and sorting of early endosomes. Nat Cell Biol 4, 124–133.PubMedGoogle Scholar
  26. Deretic, D., Huber, L.A., Ransom, N., Mancini, M., Simons, K., and Papermaster, D.S. (1995). rab8 in retinal photoreceptors may participate in rhodopsin transport and in rod outer segment disk morphogenesis. J Cell Sci 108, 215–224.PubMedGoogle Scholar
  27. Deretic, D., Williams, A.H., Ransom, N., Morel, V., Hargrave, P.A., and Arendt, A. (2005). Rhodopsin C terminus, the site of mutations causing retinal disease, regulates trafficking by binding to ADPribosylation factor 4 (ARF4). Proc Natl Acad Sci U S A 102, 3301–3306.PubMedGoogle Scholar
  28. Dishinger, J.F., Kee, H.L., Jenkins, P.M., Fan, S., Hurd, T.W., Hammond, J.W., Truong, Y.N., Margolis, B., Martens, J.R., and Verhey, K.J. (2010). Ciliary entry of the kinesin-2 motor KIF17 is regulated by importin-beta2 and RanGTP. Nat Cell Biol 12, 703–710.PubMedGoogle Scholar
  29. Donovan, S., Shannon, K.M., and Bollag, G. (2002). GTPase activating proteins: critical regulators of intracellular signaling. Biochim Biophys Acta 1602, 23–45.PubMedGoogle Scholar
  30. Duldulao, N.A., Lee, S., and Sun, Z. (2009). Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion. Development 136, 4033–4042.PubMedGoogle Scholar
  31. Eggenschwiler, J.T., Bulgakov, O.V., Qin, J., Li, T., and Anderson, K.V. (2006). Mouse Rab23 regulates hedgehog signaling from smoothened to Gli proteins. Dev Biol 290, 1–12.PubMedGoogle Scholar
  32. Eley, L., Yates, L.M., and Goodship, J.A. (2005). Cilia and disease. Curr Opin Genet Dev 15, 308–314.PubMedGoogle Scholar
  33. Essner, J.J., Vogan, K.J., Wagner, M.K., Tabin, C.J., Yost, H.J., and Brueckner, M. (2002). Conserved function for embryonic nodal cilia. Nature 418, 37–38.PubMedGoogle Scholar
  34. Evans, R.J., Schwarz, N., Nagel-Wolfrum, K., Wolfrum, U., Hardcastle, A.J., and Cheetham, M.E. (2010). The retinitis pigmentosa protein RP2 links pericentriolar vesicle transport between the Golgi and the primary cilium. Hum Mol Genet 19, 1358–1367.PubMedGoogle Scholar
  35. Fan, Y., Esmail, M.A., Ansley, S.J., Blacque, O.E., Boroevich, K., Ross, A.J., Moore, S.J., Badano, J.L., May-Simera, H., Compton, D.S., et al. (2004). Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet 36, 989–993.PubMedGoogle Scholar
  36. Fielding, A.B., Schonteich, E., Matheson, J., Wilson, G., Yu, X., Hickson, G.R., Srivastava, S., Baldwin, S.A., Prekeris, R., and Gould, G.W. (2005). Rab11-FIP3 and FIP4 interact with Arf6 and the exocyst to control membrane traffic in cytokinesis. EMBO J 24, 3389–3399.PubMedGoogle Scholar
  37. Fliegauf, M., Benzing, T., and Omran, H. (2007). When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol 8, 880–893.PubMedGoogle Scholar
  38. Follit, J.A., Li, L., Vucica, Y., and Pazour, G.J. (2010). The cytoplasmic tail of fibrocystin contains a ciliary targeting sequence. J Cell Biol 188, 21–28.PubMedGoogle Scholar
  39. Fukushige, T., Siddiqui, Z.K., Chou, M., Culotti, J.G., Gogonea, C.B., Siddiqui, S.S., and Hamelin, M. (1999). MEC-12, an alpha-tubulin required for touch sensitivity in C. elegans. J Cell Sci 112, 395–403.PubMedGoogle Scholar
  40. Geng, L., Okuhara, D., Yu, Z., Tian, X., Cai, Y., Shibazaki, S., and Somlo, S. (2006). Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif. J Cell Sci 119, 1383–1395.PubMedGoogle Scholar
  41. Gerdes, J.M., Davis, E.E., and Katsanis, N. (2009). The vertebrate primary cilium in development, homeostasis, and disease. Cell 137, 32–45.PubMedGoogle Scholar
  42. Gherman, A., Davis, E.E., and Katsanis, N. (2006). The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia. Nat Genet 38, 961–962.PubMedGoogle Scholar
  43. Goetz, S.C., and Anderson, K.V. (2010). The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11, 331–344.PubMedGoogle Scholar
  44. Grayson, C., Bartolini, F., Chapple, J.P., Willison, K.R., Bhamidipati, A., Lewis, S.A., Luthert, P.J., Hardcastle, A.J., Cowan, N.J., and Cheetham, M.E. (2002). Localization in the human retina of the Xlinked retinitis pigmentosa protein RP2, its homologue cofactor C and the RP2 interacting protein Arl3. Hum Mol Genet 11, 3065–3074.PubMedGoogle Scholar
  45. Grozinger, C.M., Hassig, C.A., and Schreiber, S.L. (1999). Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc Natl Acad Sci U S A 96, 4868–4873.PubMedGoogle Scholar
  46. Guo, W., Roth, D., Walch-Solimena, C., and Novick, P. (1999). The exocyst is an effector for Sec4p, targeting secretory vesicles to sites of exocytosis. EMBO J 18, 1071–1080.PubMedGoogle Scholar
  47. Hayes, G.L., Brown, F.C., Haas, A.K., Nottingham, R.M., Barr, F.A., and Pfeffer, S.R. (2009). Multiple Rab GTPase binding sites in GCC185 suggest a model for vesicle tethering at the trans-Golgi. Mol Biol Cell 20, 209–217.PubMedGoogle Scholar
  48. He, B., and Guo, W. (2009). The exocyst complex in polarized exocytosis. Curr Opin Cell Biol 21, 537–542.PubMedGoogle Scholar
  49. Hori, Y., Kobayashi, T., Kikko, Y., Kontani, K., and Katada, T. (2008). Domain architecture of the atypical Arf-family GTPase Arl13b involved in cilia formation. Biochem Biophys Res Commun 373, 119–124.PubMedGoogle Scholar
  50. Hu, J., Bae, Y.K., Knobel, K.M., and Barr, M.M. (2006). Casein kinase II and calcineurin modulate TRPP function and ciliary localization. Mol Biol Cell 17, 2200–2211.PubMedGoogle Scholar
  51. Hu, J., and Barr, M.M. (2005). ATP-2 interacts with the PLAT domain of LOV-1 and is involved in Caenorhabditis elegans polycystin signaling. Mol Biol Cell 16, 458–469.PubMedGoogle Scholar
  52. Hu, J., Wittekind, S.G., and Barr, M.M. (2007). STAM and Hrs downregulate ciliary TRP receptors. Mol Biol Cell 18, 3277–3289.PubMedGoogle Scholar
  53. Huangfu, D., and Anderson, K.V. (2005). Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A 102, 11325–11330.PubMedGoogle Scholar
  54. Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., Yoshida, M., Wang, X.F., and Yao, T.P. (2002). HDAC6 is a microtubule-associated deacetylase. Nature 417, 455–458.PubMedGoogle Scholar
  55. Jaffe, A.B., and Hall, A. (2005). Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21, 247–269.PubMedGoogle Scholar
  56. Jauregui, A.R., and Barr, M.M. (2005). Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors. Exp Cell Res 305, 333–342.PubMedGoogle Scholar
  57. Jauregui, A.R., Nguyen, K.C., Hall, D.H., and Barr, M.M. (2008). The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure. J Cell Biol 180, 973–988.PubMedGoogle Scholar
  58. Jenkins, D., Seelow, D., Jehee, F.S., Perlyn, C.A., Alonso, L.G., Bueno, D.F., Donnai, D., Josifova, D., Mathijssen, I.M., Morton, J. E., et al. (2007). RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet 80, 1162–1170.PubMedGoogle Scholar
  59. Jenkins, P.M., Hurd, T.W., Zhang, L., McEwen, D.P., Brown, R.L., Margolis, B., Verhey, K.J., and Martens, J.R. (2006). Ciliary targeting of olfactory CNG channels requires the CNGB1b subunit and the kinesin-2 motor protein, KIF17. Curr Biol 16, 1211–1216.PubMedGoogle Scholar
  60. Jin, H., White, S.R., Shida, T., Schulz, S., Aguiar, M., Gygi, S.P., Bazan, J.F., and Nachury, M.V. (2010). The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 141, 1208–1219.PubMedGoogle Scholar
  61. Kaplan, O.I., Molla-Herman, A., Cevik, S., Ghossoub, R., Kida, K., Kimura, Y., Jenkins, P., Martens, J.R., Setou, M., Benmerah, A., et al. (2010). The AP-1 clathrin adaptor facilitates cilium formation and functions with RAB-8 in C. elegans ciliary membrane transport. J Cell Sci 123, 3966–3977.PubMedGoogle Scholar
  62. Kim, J., Krishnaswami, S.R., and Gleeson, J.G. (2008). CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium. Hum Mol Genet 17, 3796–3805.PubMedGoogle Scholar
  63. Knobel, K.M., Peden, E.M., and Barr, M.M. (2008). Distinct protein domains regulate ciliary targeting and function of C. elegans PKD-2. Exp Cell Res 314, 825–833.PubMedGoogle Scholar
  64. Knödler, A., Feng, S., Zhang, J., Zhang, X., Das, A., Peränen, J., and Guo, W. (2010). Coordination of Rab8 and Rab11 in primary ciliogenesis. Proc Natl Acad Sci U S A 107, 6346–6351.PubMedGoogle Scholar
  65. Kovacs, J.J., Murphy, P.J., Gaillard, S., Zhao, X., Wu, J.T., Nicchitta, C.V., Yoshida, M., Toft, D.O., Pratt, W.B., and Yao, T.P. (2005). HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 18, 601–607.PubMedGoogle Scholar
  66. Kozminski, K.G., Forscher, P., and Rosenbaum, J.L. (1998). Three flagellar motilities in Chlamydomonas unrelated to flagellar beating. Video supplement. Cell Motil Cytoskeleton 39, 347–348.PubMedGoogle Scholar
  67. Lechtreck, K.F., Johnson, E.C., Sakai, T., Cochran, D., Ballif, B.A., Rush, J., Pazour, G.J., Ikebe, M., and Witman, G.B. (2009). The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. J Cell Biol 187, 1117–1132.PubMedGoogle Scholar
  68. Li, Y., Wei, Q., Zhang, Y., Ling, K., and Hu, J. (2010). The small GTPases ARL-13 and ARL-3 coordinate intraflagellar transport and ciliogenesis. J Cell Biol 189, 1039–1051.PubMedGoogle Scholar
  69. Liu, Q., Tan, G., Levenkova, N., Li, T., Pugh, E.N. Jr, Rux, J.J., Speicher, D.W., and Pierce, E.A. (2007). The proteome of the mouse photoreceptor sensory cilium complex. Mol Cell Proteomics 6, 1299–1317.PubMedGoogle Scholar
  70. Loktev, A.V., Zhang, Q., Beck, J.S., Searby, C.C., Scheetz, T.E., Bazan, J.F., Slusarski, D.C., Sheffield, V.C., Jackson, P.K., and Nachury, M.V. (2008). A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell 15, 854–865.PubMedGoogle Scholar
  71. Lowy, D.R., and Willumsen, B.M. (1993). Function and regulation of ras. Annu Rev Biochem 62, 851–891.PubMedGoogle Scholar
  72. Lundquist, E.A. (2006). Small GTPases. WormBook Jan 17, 1–18. Scholar
  73. Mak, H.Y., Nelson, L.S., Basson, M., Johnson, C.D., and Ruvkun, G. (2006). Polygenic control of Caenorhabditis elegans fat storage. Nat Genet 38, 363–368.PubMedGoogle Scholar
  74. Marshall, W.F. (2008). The cell biological basis of ciliary disease. J Cell Biol 180, 17–21.PubMedGoogle Scholar
  75. May, S.R., Ashique, A.M., Karlen, M., Wang, B., Shen, Y., Zarbalis, K., Reiter, J., Ericson, J., and Peterson, A.S. (2005). Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol 287, 378–389.PubMedGoogle Scholar
  76. Mazelova, J., Astuto-Gribble, L., Inoue, H., Tam, B.M., Schonteich, E., Prekeris, R., Moritz, O.L., Randazzo, P.A., and Deretic, D. (2009a). Ciliary targeting motif VxPx directs assembly of a trafficking module through Arf4. EMBO J 28, 183–192.PubMedGoogle Scholar
  77. Mazelova, J., Ransom, N., Astuto-Gribble, L., Wilson, M.C., and Deretic, D. (2009b). Syntaxin 3 and SNAP-25 pairing, regulated by omega-3 docosahexaenoic acid, controls the delivery of rhodopsin for the biogenesis of cilia-derived sensory organelles, the rod outer segments. J Cell Sci 122, 2003–2013.PubMedGoogle Scholar
  78. Mello, C., and Fire, A. (1995). DNA transformation. Methods Cell Biol 48, 451–482.PubMedGoogle Scholar
  79. Moritz, O.L., Tam, B.M., Hurd, L.L., Peränen, J., Deretic, D., and Papermaster, D.S. (2001). Mutant rab8 Impairs docking and fusion of rhodopsin-bearing post-Golgi membranes and causes cell death of transgenic Xenopus rods. Mol Biol Cell 12, 2341–2351.PubMedGoogle Scholar
  80. Mukhopadhyay, S., Lu, Y., Shaham, S., and Sengupta, P. (2008). Sensory signaling-dependent remodeling of olfactory cilia architecture in C. elegans. Dev Cell 14, 762–774.PubMedGoogle Scholar
  81. Myers, K.R., and Casanova, J.E. (2008). Regulation of actin cytoskeleton dynamics by Arf-family GTPases. Trends Cell Biol 18, 184–192.PubMedGoogle Scholar
  82. Nachury, M.V., Loktev, A.V., Zhang, Q., Westlake, C.J., Peränen, J., Merdes, A., Slusarski, D.C., Scheller, R.H., Bazan, J.F., Sheffield, V.C., et al. (2007). A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129, 1201–1213.PubMedGoogle Scholar
  83. Nonaka, S., Tanaka, Y., Okada, Y., Takeda, S., Harada, A., Kanai, Y., Kido, M., and Hirokawa, N. (1998). Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95, 829–837.PubMedGoogle Scholar
  84. Omori, Y., Zhao, C., Saras, A., Mukhopadhyay, S., Kim, W., Furukawa, T., Sengupta, P., Veraksa, A., and Malicki, J. (2008). Elipsa is an early determinant of ciliogenesis that links the IFT particle to membrane-associated small GTPase Rab8. Nat Cell Biol 10, 437–444.PubMedGoogle Scholar
  85. Orozco, J.T., Wedaman, K.P., Signor, D., Brown, H., Rose, L., and Scholey, J.M. (1999). Movement of motor and cargo along cilia. Nature 398, 674.PubMedGoogle Scholar
  86. Ou, G., Blacque, O.E., Snow, J.J., Leroux, M.R., and Scholey, J.M. (2005). Functional coordination of intraflagellar transport motors. Nature 436, 583–587.PubMedGoogle Scholar
  87. Ou, G., Koga, M., Blacque, O.E., Murayama, T., Ohshima, Y., Schafer, J.C., Li, C., Yoder, B.K., Leroux, M.R., and Scholey, J.M. (2007). Sensory ciliogenesis in Caenorhabditis elegans: assignment of IFT components into distinct modules based on transport and phenotypic profiles. Mol Biol Cell 18, 1554–1569.PubMedGoogle Scholar
  88. Oztan, A., Silvis, M., Weisz, O.A., Bradbury, N.A., Hsu, S.C., Goldenring, J.R., Yeaman, C., and Apodaca, G. (2007). Exocyst requirement for endocytic traffic directed toward the apical and basolateral poles of polarized MDCK cells. Mol Biol Cell 18, 3978–3992.PubMedGoogle Scholar
  89. Peden, E.M., and Barr, M.M. (2005). The KLP-6 kinesin is required for male mating behaviors and polycystin localization in Caenorhabditis elegans. Curr Biol 15, 394–404.PubMedGoogle Scholar
  90. Pedersen, L.B., and Rosenbaum, J.L. (2008). Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr Top Dev Biol 85, 23–61.PubMedGoogle Scholar
  91. Pereira-Leal, J.B., and Seabra, M.C. (2001). Evolution of the Rab family of small GTP-binding proteins. J Mol Biol 313, 889–901.PubMedGoogle Scholar
  92. Prigent, M., Dubois, T., Raposo, G., Derrien, V., Tenza, D., Rossé, C., Camonis, J., and Chavrier, P. (2003). ARF6 controls postendocytic recycling through its downstream exocyst complex effector. J Cell Biol 163, 1111–1121.PubMedGoogle Scholar
  93. Pugacheva, E.N., Jablonski, S.A., Hartman, T.R., Henske, E.P., and Golemis, E.A. (2007). HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 129, 1351–1363.PubMedGoogle Scholar
  94. Qin, H., Burnette, D.T., Bae, Y.K., Forscher, P., Barr, M.M., and Rosenbaum, J.L. (2005). Intraflagellar transport is required for the vectorial movement of TRPV channels in the ciliary membrane. Curr Biol 15, 1695–1699.PubMedGoogle Scholar
  95. Qin, H., Rosenbaum, J.L., and Barr, M.M. (2001). An autosomal recessive polycystic kidney disease gene homolog is involved in intraflagellar transport in C. elegans ciliated sensory neurons. Curr Biol 11, 457–461.PubMedGoogle Scholar
  96. Qin, H., Wang, Z., Diener, D., and Rosenbaum, J. (2007). Intraflagellar transport protein 27 is a small G protein involved in cell-cycle control. Curr Biol 17, 193–202.PubMedGoogle Scholar
  97. Reed, N.A., Cai, D., Blasius, T.L., Jih, G.T., Meyhofer, E., Gaertig, J., and Verhey, K.J. (2006). Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol 16, 2166–2172.PubMedGoogle Scholar
  98. Reuther, G.W., and Der, C.J. (2000). The Ras branch of small GTPases: Ras family members don’t fall far from the tree. Curr Opin Cell Biol 12, 157–165.PubMedGoogle Scholar
  99. Rogers, K.K., Wilson, P.D., Snyder, R.W., Zhang, X., Guo, W., Burrow, C.R., and Lipschutz, J.H. (2004). The exocyst localizes to the primary cilium in MDCK cells. Biochem Biophys Res Commun 319, 138–143.PubMedGoogle Scholar
  100. Rosenbaum, J.L., and Witman, G.B. (2002). Intraflagellar transport. Nat Rev Mol Cell Biol 3, 813–825.PubMedGoogle Scholar
  101. Schafer, J.C., Winkelbauer, M.E., Williams, C.L., Haycraft, C.J., Desmond, R.A., and Yoder, B.K. (2006). IFTA-2 is a conserved cilia protein involved in pathways regulating longevity and dauer formation in Caenorhabditis elegans. J Cell Sci 119, 4088–4100.PubMedGoogle Scholar
  102. Scholey, J.M. (2008). Intraflagellar transport motors in cilia: moving along the cell’s antenna. J Cell Biol 180, 23–29.PubMedGoogle Scholar
  103. Scholey, J.M., and Anderson, K.V. (2006). Intraflagellar transport and cilium-based signaling. Cell 125, 439–442.PubMedGoogle Scholar
  104. Schrick, J.J., Vogel, P., Abuin, A., Hampton, B., and Rice, D.S. (2006). ADP-ribosylation factor-like 3 is involved in kidney and photoreceptor development. Am J Pathol 168, 1288–1298.PubMedGoogle Scholar
  105. Signor, D., Wedaman, K.P., Orozco, J.T., Dwyer, N.D., Bargmann, C. I., Rose, L.S., and Scholey, J.M. (1999a). Role of a class DHC1b dynein in retrograde transport of IFT motors and IFT raft particles along cilia, but not dendrites, in chemosensory neurons of living Caenorhabditis elegans. J Cell Biol 147, 519–530.PubMedGoogle Scholar
  106. Signor, D., Wedaman, K.P., Rose, L.S., and Scholey, J.M. (1999b). Two heteromeric kinesin complexes in chemosensory neurons and sensory cilia of Caenorhabditis elegans. Mol Biol Cell 10, 345–360.PubMedGoogle Scholar
  107. Singla, V., and Reiter, J.F. (2006). The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science 313, 629–633.PubMedGoogle Scholar
  108. Sinka, R., Gillingham, A.K., Kondylis, V., and Munro, S. (2008). Golgi coiled-coil proteins contain multiple binding sites for Rab family G proteins. J Cell Biol 183, 607–615.PubMedGoogle Scholar
  109. Snow, J.J., Ou, G., Gunnarson, A.L., Walker, M.R., Zhou, H.M., Brust-Mascher, I., and Scholey, J.M. (2004). Two anterograde intraflagellar transport motors cooperate to build sensory cilia on C. elegans neurons. Nat Cell Biol 6, 1109–1113.PubMedGoogle Scholar
  110. Stenmark, H. (2009). Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 10, 513–525.PubMedGoogle Scholar
  111. Stenmark, H., Vitale, G., Ullrich, O., and Zerial, M. (1995). Rabaptin-5 is a direct effector of the small GTPase Rab5 in endocytic membrane fusion. Cell 83, 423–432.PubMedGoogle Scholar
  112. Stewart, M. (2007). Molecular mechanism of the nuclear protein import cycle. Nat Rev Mol Cell Biol 8, 195–208.PubMedGoogle Scholar
  113. Swoboda, P., Adler, H.T., and Thomas, J.H. (2000). The RFX-type transcription factor DAF-19 regulates sensory neuron cilium formation in C. elegans. Mol Cell 5, 411–421.PubMedGoogle Scholar
  114. Tabara, H., Grishok, A., and Mello, C.C. (1998). RNAi in C. elegans: soaking in the genome sequence. Science 282, 430–431.PubMedGoogle Scholar
  115. Takaki, E., Fujimoto, M., Nakahari, T., Yonemura, S., Miyata, Y., Hayashida, N., Yamamoto, K., Vallee, R.B., Mikuriya, T., Sugahara, K., et al. (2007). Heat shock transcription factor 1 is required for maintenance of ciliary beating in mice. J Biol Chem 282, 37285–37292.PubMedGoogle Scholar
  116. Tran, P.V., Haycraft, C.J., Besschetnova, T.Y., Turbe-Doan, A., Stottmann, R.W., Herron, B.J., Chesebro, A.L., Qiu, H., Scherz, P.J., Shah, J.V., et al. (2008). THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat Genet 40, 403–410.PubMedGoogle Scholar
  117. Tsang, W.Y., Bossard, C., Khanna, H., Peränen, J., Swaroop, A., Malhotra, V., and Dynlacht, B.D. (2008). CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficient in human ciliary disease. Dev Cell 15, 187–197.PubMedGoogle Scholar
  118. Vitale, G., Rybin, V., Christoforidis, S., Thornqvist, P., McCaffrey, M., Stenmark, H., and Zerial, M. (1998). Distinct Rab-binding domains mediate the interaction of Rabaptin-5 with GTP-bound Rab4 and Rab5. EMBO J 17, 1941–1951.PubMedGoogle Scholar
  119. Watnick, T., and Germino, G. (2003). From cilia to cyst. Nat Genet 34, 355–356.PubMedGoogle Scholar
  120. Weis, K. (2003). Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle. Cell 112, 441–451.PubMedGoogle Scholar
  121. Wennerberg, K., Rossman, K.L., and Der, C.J. (2005). The Ras superfamily at a glance. J Cell Sci 118, 843–846.PubMedGoogle Scholar
  122. Wiens, C.J., Tong, Y., Esmail, M.A., Oh, E., Gerdes, J.M., Wang, J., Tempel, W., Rattner, J.B., Katsanis, N., Park, H.W.,et al. (2010). Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling. J Biol Chem 285, 16218–16230.PubMedGoogle Scholar
  123. Williams, C.L., Masyukova, S.V., and Yoder, B.K. (2010). Normal ciliogenesis requires synergy between the cystic kidney disease genes MKS-3 and NPHP-4. J Am Soc Nephrol 21, 782–793.PubMedGoogle Scholar
  124. Williams, C.L., Winkelbauer, M.E., Schafer, J.C., Michaud, E.J., and Yoder, B.K. (2008). Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis elegans ciliogenesis. Mol Biol Cell 19, 2154–2168.PubMedGoogle Scholar
  125. Winter-Vann, A.M., and Casey, P.J. (2005). Post-prenylationprocessing enzymes as new targets in oncogenesis. Nat Rev Cancer 5, 405–412.PubMedGoogle Scholar
  126. Wolf, M.T., Lee, J., Panther, F., Otto, E.A., Guan, K.L., and Hildebrandt, F. (2005). Expression and phenotype analysis of the nephrocystin-1 and nephrocystin-4 homologs in Caenorhabditis elegans. J Am Soc Nephrol 16, 676–687.PubMedGoogle Scholar
  127. Wu, S., Mehta, S.Q., Pichaud, F., Bellen, H.J., and Quiocho, F.A. (2005). Sec15 interacts with Rab11 via a novel domain and affects Rab11 localization in vivo. Nat Struct Mol Biol 12, 879–885.PubMedGoogle Scholar
  128. Yoshimura, S., Egerer, J., Fuchs, E., Haas, A.K., and Barr, F.A. (2007). Functional dissection of Rab GTPases involved in primary cilium formation. J Cell Biol 178, 363–369.PubMedGoogle Scholar
  129. Zaghloul, N.A., and Katsanis, N. (2009). Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J Clin Invest 119, 428–437.PubMedGoogle Scholar
  130. Zerial, M., and McBride, H. (2001). Rab proteins as membrane organizers. Nat Rev Mol Cell Biol 2, 107–117.PubMedGoogle Scholar
  131. Zhang, X., Yuan, Z., Zhang, Y., Yong, S., Salas-Burgos, A., Koomen, J., Olashaw, N., Parsons, J.T., Yang, X.J., Dent, S.R.,et al. (2007). HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol Cell 27, 197–213.PubMedGoogle Scholar
  132. Zhang, X.M., Ellis, S., Sriratana, A., Mitchell, C.A., and Rowe, T. (2004). Sec15 is an effector for the Rab11 GTPase in mammalian cells. J Biol Chem 279, 43027–43034.PubMedGoogle Scholar
  133. Zheng, Y. (2004). G protein control of microtubule assembly. Annu Rev Cell Dev Biol 20, 867–894.PubMedGoogle Scholar
  134. Zuo, X., Guo, W., and Lipschutz, J.H. (2009). The exocyst protein Sec10 is necessary for primary ciliogenesis and cystogenesis in vitro. Mol Biol Cell 20, 2522–2529.PubMedGoogle Scholar
  135. Zhou, C., Cunningham, L., Marcus, A.I., Li, Y., and Kahn, R.A. (2006). Arl2 and Arl3 regulate different microtubule-dependent processes. Mol Biol Cell 17, 2476–2487.PubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Department of Nephrology and HypertensionMayo ClinicRochesterUSA
  2. 2.Translational PKD CenterMayo ClinicRochesterUSA
  3. 3.Department of Biochemistry and Molecular BiologyMayo ClinicRochesterUSA

Personalised recommendations