Skip to main content
Protein & Cell logoLink to Protein & Cell
. 2011 Feb 20;2(1):13–25. doi: 10.1007/s13238-011-1004-7

Small GTPases and cilia

Yujie Li 1, Jinghua Hu 1,2,3,
PMCID: PMC3858892  NIHMSID: NIHMS530226  PMID: 21337006

Abstract

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.

Keywords: Small GTPase, cilia, ciliopathy

Footnotes

An erratum to this article can be found at http://dx.doi.org/10.1007/s13238-011-1030-5

References

  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. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature. 2003;425:628–633. doi: 10.1038/nature02030. [DOI] [PubMed] [Google Scholar]
  2. Avidor-Reiss T., Maer A.M., Koundakjian E., Polyanovsky A., Keil T., Subramaniam S., Zuker C.S. Decoding cilia function: defining specialized genes required for compartmentalized cilia biogenesis. Cell. 2004;117:527–539. doi: 10.1016/s0092-8674(04)00412-x. [DOI] [PubMed] [Google Scholar]
  3. Babbey C.M., Bacallao R.L., Dunn K.W. Rab10 associates with primary cilia and the exocyst complex in renal epithelial cells. Am J Physiol Renal Physiol. 2010;299:F495–F506. doi: 10.1152/ajprenal.00198.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Badano J.L., Mitsuma N., Beales P.L., Katsanis N. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet. 2006;7:125–148. doi: 10.1146/annurev.genom.7.080505.115610. [DOI] [PubMed] [Google Scholar]
  5. Bae Y.K., Lyman-Gingerich J., Barr M.M., Knobel K.M. Identification of genes involved in the ciliary trafficking of C. elegans PKD-2. Dev Dyn. 2008;237:2021–2029. doi: 10.1002/dvdy.21531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bae Y.K., Qin H., Knobel K.M., Hu J., Rosenbaum J.L., Barr M.M. General and cell-type specific mechanisms target TRPP2/PKD-2 to cilia. Development. 2006;133:3859–3870. doi: 10.1242/dev.02555. [DOI] [PubMed] [Google Scholar]
  7. Barr M.M. Caenorhabditis elegans as a model to study renal development and disease: sexy cilia. J Am Soc Nephrol. 2005;16:305–312. doi: 10.1681/ASN.2004080645. [DOI] [PubMed] [Google Scholar]
  8. Barr M.M., DeModena J., Braun D., Nguyen C.Q., Hall D.H., Sternberg P.W. The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway. Curr Biol. 2001;11:1341–1346. doi: 10.1016/s0960-9822(01)00423-7. [DOI] [PubMed] [Google Scholar]
  9. Barr M.M., Sternberg P.W. A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans. Nature. 1999;401:386–389. doi: 10.1038/43913. [DOI] [PubMed] [Google Scholar]
  10. Berbari N.F., Lewis J.S., Bishop G.A., Askwith C.C., Mykytyn K. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci U S A. 2008;105:4242–4246. doi: 10.1073/pnas.0711027105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bernards A., Settleman J. GAP control: regulating the regulators of small GTPases. Trends Cell Biol. 2004;14:377–385. doi: 10.1016/j.tcb.2004.05.003. [DOI] [PubMed] [Google 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. Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins. J Cell Sci. 2009;122:611–624. doi: 10.1242/jcs.028621. [DOI] [PMC free article] [PubMed] [Google 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. Functional genomics of the cilium, a sensory organelle. Curr Biol. 2005;15:935–941. doi: 10.1016/j.cub.2005.04.059. [DOI] [PubMed] [Google 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. Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev. 2004;18:1630–1642. doi: 10.1101/gad.1194004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Boehlke C., Bashkurov M., Buescher A., Krick T., John A.K., Nitschke R., Walz G., Kuehn E.W. Differential role of Rab proteins in ciliary trafficking: Rab23 regulates smoothened levels. J Cell Sci. 2010;123:1460–1467. doi: 10.1242/jcs.058883. [DOI] [PubMed] [Google Scholar]
  16. Boguski M.S., McCormick F. Proteins regulating Ras and its relatives. Nature. 1993;366:643–654. doi: 10.1038/366643a0. [DOI] [PubMed] [Google Scholar]
  17. Caspary T., Larkins C.E., Anderson K.V. The graded response to Sonic Hedgehog depends on cilia architecture. Dev Cell. 2007;12:767–778. doi: 10.1016/j.devcel.2007.03.004. [DOI] [PubMed] [Google Scholar]
  18. Cevik S., Hori Y., Kaplan O.I., Kida K., Toivenon T., Foley-Fisher C., Cottell D., Katada T., Kontani K., Blacque O.E. Joubert syndrome Arl13b functions at ciliary membranes and stabilizes protein transport in Caenorhabditis elegans. J Cell Biol. 2010;188:953–969. doi: 10.1083/jcb.200908133. [DOI] [PMC free article] [PubMed] [Google 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. Identification of ciliary and ciliopathy genes in Caenorhabditis elegans through comparative genomics. Genome Biol. 2006;7:R126. doi: 10.1186/gb-2006-7-12-r126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Cherfils J., Chardin P. GEFs: structural basis for their activation of small GTP-binding proteins. Trends Biochem Sci. 1999;24:306–311. doi: 10.1016/s0968-0004(99)01429-2. [DOI] [PubMed] [Google 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. Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3) Am J Hum Genet. 2004;75:475–484. doi: 10.1086/423903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Clarke P.R., Zhang C. Spatial and temporal coordination of mitosis by Ran GTPase. Nat Rev Mol Cell Biol. 2008;9:464–477. doi: 10.1038/nrm2410. [DOI] [PubMed] [Google Scholar]
  23. Cuvillier A., Redon F., Antoine J.C., Chardin P., DeVos T., Merlin G. LdARL-3A, a Leishmania promastigote-specific ADP-ribosylation factor-like protein, is essential for flagellum integrity. J Cell Sci. 2000;113:2065–2074. doi: 10.1242/jcs.113.11.2065. [DOI] [PubMed] [Google Scholar]
  24. D’souza-Schorey C., Chavrier P. ARF proteins: roles in membrane traffic and beyond. Nat Rev Mol Cell Biol. 2006;7:347–358. doi: 10.1038/nrm1910. [DOI] [PubMed] [Google Scholar]
  25. de Renzis S., Sönnichsen B., Zerial M. Divalent Rab effectors regulate the sub-compartmental organization and sorting of early endosomes. Nat Cell Biol. 2002;4:124–133. doi: 10.1038/ncb744. [DOI] [PubMed] [Google Scholar]
  26. Deretic D., Huber L.A., Ransom N., Mancini M., Simons K., Papermaster D.S. rab8 in retinal photoreceptors may participate in rhodopsin transport and in rod outer segment disk morphogenesis. J Cell Sci. 1995;108:215–224. doi: 10.1242/jcs.108.1.215. [DOI] [PubMed] [Google Scholar]
  27. Deretic D., Williams A.H., Ransom N., Morel V., Hargrave P.A., Arendt A. 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. 2005;102:3301–3306. doi: 10.1073/pnas.0500095102. [DOI] [PMC free article] [PubMed] [Google 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., Verhey K.J. Ciliary entry of the kinesin-2 motor KIF17 is regulated by importin-beta2 and RanGTP. Nat Cell Biol. 2010;12:703–710. doi: 10.1038/ncb2073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Donovan S., Shannon K.M., Bollag G. GTPase activating proteins: critical regulators of intracellular signaling. Biochim Biophys Acta. 2002;1602:23–45. doi: 10.1016/s0304-419x(01)00041-5. [DOI] [PubMed] [Google Scholar]
  30. Duldulao N.A., Lee S., Sun Z. Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion. Development. 2009;136:4033–4042. doi: 10.1242/dev.036350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Eggenschwiler J.T., Bulgakov O.V., Qin J., Li T., Anderson K.V. Mouse Rab23 regulates hedgehog signaling from smoothened to Gli proteins. Dev Biol. 2006;290:1–12. doi: 10.1016/j.ydbio.2005.09.022. [DOI] [PubMed] [Google Scholar]
  32. Eley L., Yates L.M., Goodship J.A. Cilia and disease. Curr Opin Genet Dev. 2005;15:308–314. doi: 10.1016/j.gde.2005.04.008. [DOI] [PubMed] [Google Scholar]
  33. Essner J.J., Vogan K.J., Wagner M.K., Tabin C.J., Yost H.J., Brueckner M. Conserved function for embryonic nodal cilia. Nature. 2002;418:37–38. doi: 10.1038/418037a. [DOI] [PubMed] [Google Scholar]
  34. Evans R.J., Schwarz N., Nagel-Wolfrum K., Wolfrum U., Hardcastle A.J., Cheetham M.E. The retinitis pigmentosa protein RP2 links pericentriolar vesicle transport between the Golgi and the primary cilium. Hum Mol Genet. 2010;19:1358–1367. doi: 10.1093/hmg/ddq012. [DOI] [PubMed] [Google 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. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet. 2004;36:989–993. doi: 10.1038/ng1414. [DOI] [PubMed] [Google Scholar]
  36. Fielding A.B., Schonteich E., Matheson J., Wilson G., Yu X., Hickson G.R., Srivastava S., Baldwin S.A., Prekeris R., Gould G.W. Rab11-FIP3 and FIP4 interact with Arf6 and the exocyst to control membrane traffic in cytokinesis. EMBO J. 2005;24:3389–3399. doi: 10.1038/sj.emboj.7600803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Fliegauf M., Benzing T., Omran H. When cilia go bad: cilia defects and ciliopathies. Nat Rev Mol Cell Biol. 2007;8:880–893. doi: 10.1038/nrm2278. [DOI] [PubMed] [Google Scholar]
  38. Follit J.A., Li L., Vucica Y., Pazour G.J. The cytoplasmic tail of fibrocystin contains a ciliary targeting sequence. J Cell Biol. 2010;188:21–28. doi: 10.1083/jcb.200910096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Fukushige T., Siddiqui Z.K., Chou M., Culotti J.G., Gogonea C.B., Siddiqui S.S., Hamelin M. MEC-12, an alpha-tubulin required for touch sensitivity in C. elegans. J Cell Sci. 1999;112:395–403. doi: 10.1242/jcs.112.3.395. [DOI] [PubMed] [Google Scholar]
  40. Geng L., Okuhara D., Yu Z., Tian X., Cai Y., Shibazaki S., Somlo S. Polycystin-2 traffics to cilia independently of polycystin-1 by using an N-terminal RVxP motif. J Cell Sci. 2006;119:1383–1395. doi: 10.1242/jcs.02818. [DOI] [PubMed] [Google Scholar]
  41. Gerdes J.M., Davis E.E., Katsanis N. The vertebrate primary cilium in development, homeostasis, and disease. Cell. 2009;137:32–45. doi: 10.1016/j.cell.2009.03.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Gherman A., Davis E.E., Katsanis N. The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia. Nat Genet. 2006;38:961–962. doi: 10.1038/ng0906-961. [DOI] [PubMed] [Google Scholar]
  43. Goetz S.C., Anderson K.V. The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet. 2010;11:331–344. doi: 10.1038/nrg2774. [DOI] [PMC free article] [PubMed] [Google 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., Cheetham M.E. 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. 2002;11:3065–3074. doi: 10.1093/hmg/11.24.3065. [DOI] [PubMed] [Google Scholar]
  45. Grozinger C.M., Hassig C.A., Schreiber S.L. Three proteins define a class of human histone deacetylases related to yeast Hda1p. Proc Natl Acad Sci U S A. 1999;96:4868–4873. doi: 10.1073/pnas.96.9.4868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Guo W., Roth D., Walch-Solimena C., Novick P. The exocyst is an effector for Sec4p, targeting secretory vesicles to sites of exocytosis. EMBO J. 1999;18:1071–1080. doi: 10.1093/emboj/18.4.1071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Hayes G.L., Brown F.C., Haas A.K., Nottingham R.M., Barr F.A., Pfeffer S.R. Multiple Rab GTPase binding sites in GCC185 suggest a model for vesicle tethering at the trans-Golgi. Mol Biol Cell. 2009;20:209–217. doi: 10.1091/mbc.E08-07-0740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. He B., Guo W. The exocyst complex in polarized exocytosis. Curr Opin Cell Biol. 2009;21:537–542. doi: 10.1016/j.ceb.2009.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Hori Y., Kobayashi T., Kikko Y., Kontani K., Katada T. Domain architecture of the atypical Arf-family GTPase Arl13b involved in cilia formation. Biochem Biophys Res Commun. 2008;373:119–124. doi: 10.1016/j.bbrc.2008.06.001. [DOI] [PubMed] [Google Scholar]
  50. Hu J., Bae Y.K., Knobel K.M., Barr M.M. Casein kinase II and calcineurin modulate TRPP function and ciliary localization. Mol Biol Cell. 2006;17:2200–2211. doi: 10.1091/mbc.E05-10-0935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Hu J., Barr M.M. ATP-2 interacts with the PLAT domain of LOV-1 and is involved in Caenorhabditis elegans polycystin signaling. Mol Biol Cell. 2005;16:458–469. doi: 10.1091/mbc.E04-09-0851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Hu J., Wittekind S.G., Barr M.M. STAM and Hrs downregulate ciliary TRP receptors. Mol Biol Cell. 2007;18:3277–3289. doi: 10.1091/mbc.E07-03-0239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Huangfu D., Anderson K.V. Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A. 2005;102:11325–11330. doi: 10.1073/pnas.0505328102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Hubbert C., Guardiola A., Shao R., Kawaguchi Y., Ito A., Nixon A., Yoshida M., Wang X.F., Yao T.P. HDAC6 is a microtubule-associated deacetylase. Nature. 2002;417:455–458. doi: 10.1038/417455a. [DOI] [PubMed] [Google Scholar]
  55. Jaffe A.B., Hall A. Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol. 2005;21:247–269. doi: 10.1146/annurev.cellbio.21.020604.150721. [DOI] [PubMed] [Google Scholar]
  56. Jauregui A.R., Barr M.M. Functional characterization of the C. elegans nephrocystins NPHP-1 and NPHP-4 and their role in cilia and male sensory behaviors. Exp Cell Res. 2005;305:333–342. doi: 10.1016/j.yexcr.2005.01.008. [DOI] [PubMed] [Google Scholar]
  57. Jauregui A.R., Nguyen K.C., Hall D.H., Barr M.M. The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure. J Cell Biol. 2008;180:973–988. doi: 10.1083/jcb.200707090. [DOI] [PMC free article] [PubMed] [Google 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. RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet. 2007;80:1162–1170. doi: 10.1086/518047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Jenkins P.M., Hurd T.W., Zhang L., McEwen D.P., Brown R.L., Margolis B., Verhey K.J., Martens J.R. Ciliary targeting of olfactory CNG channels requires the CNGB1b subunit and the kinesin-2 motor protein, KIF17. Curr Biol. 2006;16:1211–1216. doi: 10.1016/j.cub.2006.04.034. [DOI] [PubMed] [Google Scholar]
  60. Jin H., White S.R., Shida T., Schulz S., Aguiar M., Gygi S.P., Bazan J.F., Nachury M.V. The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell. 2010;141:1208–1219. doi: 10.1016/j.cell.2010.05.015. [DOI] [PMC free article] [PubMed] [Google 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. The AP-1 clathrin adaptor facilitates cilium formation and functions with RAB-8 in C. elegans ciliary membrane transport. J Cell Sci. 2010;123:3966–3977. doi: 10.1242/jcs.073908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Kim J., Krishnaswami S.R., Gleeson J.G. CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium. Hum Mol Genet. 2008;17:3796–3805. doi: 10.1093/hmg/ddn277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Knobel K.M., Peden E.M., Barr M.M. Distinct protein domains regulate ciliary targeting and function of C. elegans PKD-2. Exp Cell Res. 2008;314:825–833. doi: 10.1016/j.yexcr.2007.10.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Knödler A., Feng S., Zhang J., Zhang X., Das A., Peränen J., Guo W. Coordination of Rab8 and Rab11 in primary ciliogenesis. Proc Natl Acad Sci U S A. 2010;107:6346–6351. doi: 10.1073/pnas.1002401107. [DOI] [PMC free article] [PubMed] [Google 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., Yao T.P. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell. 2005;18:601–607. doi: 10.1016/j.molcel.2005.04.021. [DOI] [PubMed] [Google Scholar]
  66. Kozminski K.G., Forscher P., Rosenbaum J.L. Three flagellar motilities in Chlamydomonas unrelated to flagellar beating. Video supplement. Cell Motil Cytoskeleton. 1998;39:347–348. [PubMed] [Google Scholar]
  67. Lechtreck K.F., Johnson E.C., Sakai T., Cochran D., Ballif B.A., Rush J., Pazour G.J., Ikebe M., Witman G.B. The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. J Cell Biol. 2009;187:1117–1132. doi: 10.1083/jcb.200909183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Li Y., Wei Q., Zhang Y., Ling K., Hu J. The small GTPases ARL-13 and ARL-3 coordinate intraflagellar transport and ciliogenesis. J Cell Biol. 2010;189:1039–1051. doi: 10.1083/jcb.200912001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Liu Q., Tan G., Levenkova N., Li T., Pugh E.N., Jr, Rux J.J., Speicher D.W., Pierce E.A. The proteome of the mouse photoreceptor sensory cilium complex. Mol Cell Proteomics. 2007;6:1299–1317. doi: 10.1074/mcp.M700054-MCP200. [DOI] [PMC free article] [PubMed] [Google 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., Nachury M.V. A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Dev Cell. 2008;15:854–865. doi: 10.1016/j.devcel.2008.11.001. [DOI] [PubMed] [Google Scholar]
  71. Lowy D.R., Willumsen B.M. Function and regulation of ras. Annu Rev Biochem. 1993;62:851–891. doi: 10.1146/annurev.bi.62.070193.004223. [DOI] [PubMed] [Google Scholar]
  72. Lundquist E.A. Small GTPases. WormBook Jan. 2006;17:1–18. doi: 10.1895/wormbook.1.67.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Mak H.Y., Nelson L.S., Basson M., Johnson C.D., Ruvkun G. Polygenic control of Caenorhabditis elegans fat storage. Nat Genet. 2006;38:363–368. doi: 10.1038/ng1739. [DOI] [PubMed] [Google Scholar]
  74. Marshall W.F. The cell biological basis of ciliary disease. J Cell Biol. 2008;180:17–21. doi: 10.1083/jcb.200710085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. May S.R., Ashique A.M., Karlen M., Wang B., Shen Y., Zarbalis K., Reiter J., Ericson J., Peterson A.S. 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. 2005;287:378–389. doi: 10.1016/j.ydbio.2005.08.050. [DOI] [PubMed] [Google Scholar]
  76. Mazelova J., Astuto-Gribble L., Inoue H., Tam B.M., Schonteich E., Prekeris R., Moritz O.L., Randazzo P.A., Deretic D. Ciliary targeting motif VxPx directs assembly of a trafficking module through Arf4. EMBO J. 2009;28:183–192. doi: 10.1038/emboj.2008.267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Mazelova J., Ransom N., Astuto-Gribble L., Wilson M.C., Deretic D. 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. 2009;122:2003–2013. doi: 10.1242/jcs.039982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Mello C., Fire A. DNA transformation. Methods Cell Biol. 1995;48:451–482. [PubMed] [Google Scholar]
  79. Moritz O.L., Tam B.M., Hurd L.L., Peränen J., Deretic D., Papermaster D.S. Mutant rab8 Impairs docking and fusion of rhodopsin-bearing post-Golgi membranes and causes cell death of transgenic Xenopus rods. Mol Biol Cell. 2001;12:2341–2351. doi: 10.1091/mbc.12.8.2341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Mukhopadhyay S., Lu Y., Shaham S., Sengupta P. Sensory signaling-dependent remodeling of olfactory cilia architecture in C. elegans. Dev Cell. 2008;14:762–774. doi: 10.1016/j.devcel.2008.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Myers K.R., Casanova J.E. Regulation of actin cytoskeleton dynamics by Arf-family GTPases. Trends Cell Biol. 2008;18:184–192. doi: 10.1016/j.tcb.2008.02.002. [DOI] [PMC free article] [PubMed] [Google 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. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell. 2007;129:1201–1213. doi: 10.1016/j.cell.2007.03.053. [DOI] [PubMed] [Google Scholar]
  83. Nonaka S., Tanaka Y., Okada Y., Takeda S., Harada A., Kanai Y., Kido M., Hirokawa N. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell. 1998;95:829–837. doi: 10.1016/s0092-8674(00)81705-5. [DOI] [PubMed] [Google Scholar]
  84. Omori Y., Zhao C., Saras A., Mukhopadhyay S., Kim W., Furukawa T., Sengupta P., Veraksa A., Malicki J. Elipsa is an early determinant of ciliogenesis that links the IFT particle to membrane-associated small GTPase Rab8. Nat Cell Biol. 2008;10:437–444. doi: 10.1038/ncb1706. [DOI] [PubMed] [Google Scholar]
  85. Orozco J.T., Wedaman K.P., Signor D., Brown H., Rose L., Scholey J.M. Movement of motor and cargo along cilia. Nature. 1999;398:674. doi: 10.1038/19448. [DOI] [PubMed] [Google Scholar]
  86. Ou G., Blacque O.E., Snow J.J., Leroux M.R., Scholey J.M. Functional coordination of intraflagellar transport motors. Nature. 2005;436:583–587. doi: 10.1038/nature03818. [DOI] [PubMed] [Google Scholar]
  87. Ou G., Koga M., Blacque O.E., Murayama T., Ohshima Y., Schafer J.C., Li C., Yoder B.K., Leroux M.R., Scholey J.M. Sensory ciliogenesis in Caenorhabditis elegans: assignment of IFT components into distinct modules based on transport and phenotypic profiles. Mol Biol Cell. 2007;18:1554–1569. doi: 10.1091/mbc.E06-09-0805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Oztan A., Silvis M., Weisz O.A., Bradbury N.A., Hsu S.C., Goldenring J.R., Yeaman C., Apodaca G. Exocyst requirement for endocytic traffic directed toward the apical and basolateral poles of polarized MDCK cells. Mol Biol Cell. 2007;18:3978–3992. doi: 10.1091/mbc.E07-02-0097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Peden E.M., Barr M.M. The KLP-6 kinesin is required for male mating behaviors and polycystin localization in Caenorhabditis elegans. Curr Biol. 2005;15:394–404. doi: 10.1016/j.cub.2004.12.073. [DOI] [PubMed] [Google Scholar]
  90. Pedersen L.B., Rosenbaum J.L. Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr Top Dev Biol. 2008;85:23–61. doi: 10.1016/S0070-2153(08)00802-8. [DOI] [PubMed] [Google Scholar]
  91. Pereira-Leal J.B., Seabra M.C. Evolution of the Rab family of small GTP-binding proteins. J Mol Biol. 2001;313:889–901. doi: 10.1006/jmbi.2001.5072. [DOI] [PubMed] [Google Scholar]
  92. Prigent M., Dubois T., Raposo G., Derrien V., Tenza D., Rossé C., Camonis J., Chavrier P. ARF6 controls postendocytic recycling through its downstream exocyst complex effector. J Cell Biol. 2003;163:1111–1121. doi: 10.1083/jcb.200305029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Pugacheva E.N., Jablonski S.A., Hartman T.R., Henske E.P., Golemis E.A. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell. 2007;129:1351–1363. doi: 10.1016/j.cell.2007.04.035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Qin H., Burnette D.T., Bae Y.K., Forscher P., Barr M.M., Rosenbaum J.L. Intraflagellar transport is required for the vectorial movement of TRPV channels in the ciliary membrane. Curr Biol. 2005;15:1695–1699. doi: 10.1016/j.cub.2005.08.047. [DOI] [PubMed] [Google Scholar]
  95. Qin H., Rosenbaum J.L., Barr M.M. An autosomal recessive polycystic kidney disease gene homolog is involved in intraflagellar transport in C. elegans ciliated sensory neurons. Curr Biol. 2001;11:457–461. doi: 10.1016/s0960-9822(01)00122-1. [DOI] [PubMed] [Google Scholar]
  96. Qin H., Wang Z., Diener D., Rosenbaum J. Intraflagellar transport protein 27 is a small G protein involved in cell-cycle control. Curr Biol. 2007;17:193–202. doi: 10.1016/j.cub.2006.12.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Reed N.A., Cai D., Blasius T.L., Jih G.T., Meyhofer E., Gaertig J., Verhey K.J. Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol. 2006;16:2166–2172. doi: 10.1016/j.cub.2006.09.014. [DOI] [PubMed] [Google Scholar]
  98. Reuther G.W., Der C.J. The Ras branch of small GTPases: Ras family members don’t fall far from the tree. Curr Opin Cell Biol. 2000;12:157–165. doi: 10.1016/s0955-0674(99)00071-x. [DOI] [PubMed] [Google Scholar]
  99. Rogers K.K., Wilson P.D., Snyder R.W., Zhang X., Guo W., Burrow C.R., Lipschutz J.H. The exocyst localizes to the primary cilium in MDCK cells. Biochem Biophys Res Commun. 2004;319:138–143. doi: 10.1016/j.bbrc.2004.04.165. [DOI] [PubMed] [Google Scholar]
  100. Rosenbaum J.L., Witman G.B. Intraflagellar transport. Nat Rev Mol Cell Biol. 2002;3:813–825. doi: 10.1038/nrm952. [DOI] [PubMed] [Google Scholar]
  101. Schafer J.C., Winkelbauer M.E., Williams C.L., Haycraft C.J., Desmond R.A., Yoder B.K. IFTA-2 is a conserved cilia protein involved in pathways regulating longevity and dauer formation in Caenorhabditis elegans. J Cell Sci. 2006;119:4088–4100. doi: 10.1242/jcs.03187. [DOI] [PubMed] [Google Scholar]
  102. Scholey J.M. Intraflagellar transport motors in cilia: moving along the cell’s antenna. J Cell Biol. 2008;180:23–29. doi: 10.1083/jcb.200709133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Scholey J.M., Anderson K.V. Intraflagellar transport and cilium-based signaling. Cell. 2006;125:439–442. doi: 10.1016/j.cell.2006.04.013. [DOI] [PubMed] [Google Scholar]
  104. Schrick J.J., Vogel P., Abuin A., Hampton B., Rice D.S. ADP-ribosylation factor-like 3 is involved in kidney and photoreceptor development. Am J Pathol. 2006;168:1288–1298. doi: 10.2353/ajpath.2006.050941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Signor D., Wedaman K.P., Orozco J.T., Dwyer N.D., Bargmann C. I., Rose L.S., Scholey J.M. 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. 1999;147:519–530. doi: 10.1083/jcb.147.3.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Signor D., Wedaman K.P., Rose L.S., Scholey J.M. Two heteromeric kinesin complexes in chemosensory neurons and sensory cilia of Caenorhabditis elegans. Mol Biol Cell. 1999;10:345–360. doi: 10.1091/mbc.10.2.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Singla V., Reiter J.F. The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science. 2006;313:629–633. doi: 10.1126/science.1124534. [DOI] [PubMed] [Google Scholar]
  108. Sinka R., Gillingham A.K., Kondylis V., Munro S. Golgi coiled-coil proteins contain multiple binding sites for Rab family G proteins. J Cell Biol. 2008;183:607–615. doi: 10.1083/jcb.200808018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Snow J.J., Ou G., Gunnarson A.L., Walker M.R., Zhou H.M., Brust-Mascher I., Scholey J.M. Two anterograde intraflagellar transport motors cooperate to build sensory cilia on C. elegans neurons. Nat Cell Biol. 2004;6:1109–1113. doi: 10.1038/ncb1186. [DOI] [PubMed] [Google Scholar]
  110. Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol. 2009;10:513–525. doi: 10.1038/nrm2728. [DOI] [PubMed] [Google Scholar]
  111. Stenmark H., Vitale G., Ullrich O., Zerial M. Rabaptin-5 is a direct effector of the small GTPase Rab5 in endocytic membrane fusion. Cell. 1995;83:423–432. doi: 10.1016/0092-8674(95)90120-5. [DOI] [PubMed] [Google Scholar]
  112. Stewart M. Molecular mechanism of the nuclear protein import cycle. Nat Rev Mol Cell Biol. 2007;8:195–208. doi: 10.1038/nrm2114. [DOI] [PubMed] [Google Scholar]
  113. Swoboda P., Adler H.T., Thomas J.H. The RFX-type transcription factor DAF-19 regulates sensory neuron cilium formation in C. elegans. Mol Cell. 2000;5:411–421. doi: 10.1016/s1097-2765(00)80436-0. [DOI] [PubMed] [Google Scholar]
  114. Tabara H., Grishok A., Mello C.C. RNAi in C. elegans: soaking in the genome sequence. Science. 1998;282:430–431. doi: 10.1126/science.282.5388.430. [DOI] [PubMed] [Google 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. Heat shock transcription factor 1 is required for maintenance of ciliary beating in mice. J Biol Chem. 2007;282:37285–37292. doi: 10.1074/jbc.M704562200. [DOI] [PubMed] [Google 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. THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat Genet. 2008;40:403–410. doi: 10.1038/ng.105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Tsang W.Y., Bossard C., Khanna H., Peränen J., Swaroop A., Malhotra V., Dynlacht B.D. CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficient in human ciliary disease. Dev Cell. 2008;15:187–197. doi: 10.1016/j.devcel.2008.07.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  118. Vitale G., Rybin V., Christoforidis S., Thornqvist P., McCaffrey M., Stenmark H., Zerial M. Distinct Rab-binding domains mediate the interaction of Rabaptin-5 with GTP-bound Rab4 and Rab5. EMBO J. 1998;17:1941–1951. doi: 10.1093/emboj/17.7.1941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Watnick T., Germino G. From cilia to cyst. Nat Genet. 2003;34:355–356. doi: 10.1038/ng0803-355. [DOI] [PubMed] [Google Scholar]
  120. Weis K. Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle. Cell. 2003;112:441–451. doi: 10.1016/s0092-8674(03)00082-5. [DOI] [PubMed] [Google Scholar]
  121. Wennerberg K., Rossman K.L., Der C.J. The Ras superfamily at a glance. J Cell Sci. 2005;118:843–846. doi: 10.1242/jcs.01660. [DOI] [PubMed] [Google 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. Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling. J Biol Chem. 2010;285:16218–16230. doi: 10.1074/jbc.M109.070953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  123. Williams C.L., Masyukova S.V., Yoder B.K. Normal ciliogenesis requires synergy between the cystic kidney disease genes MKS-3 and NPHP-4. J Am Soc Nephrol. 2010;21:782–793. doi: 10.1681/ASN.2009060597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  124. Williams C.L., Winkelbauer M.E., Schafer J.C., Michaud E.J., Yoder B.K. Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis elegans ciliogenesis. Mol Biol Cell. 2008;19:2154–2168. doi: 10.1091/mbc.E07-10-1070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  125. Winter-Vann A.M., Casey P.J. Post-prenylationprocessing enzymes as new targets in oncogenesis. Nat Rev Cancer. 2005;5:405–412. doi: 10.1038/nrc1612. [DOI] [PubMed] [Google Scholar]
  126. Wolf M.T., Lee J., Panther F., Otto E.A., Guan K.L., Hildebrandt F. Expression and phenotype analysis of the nephrocystin-1 and nephrocystin-4 homologs in Caenorhabditis elegans. J Am Soc Nephrol. 2005;16:676–687. doi: 10.1681/ASN.2003121025. [DOI] [PubMed] [Google Scholar]
  127. Wu S., Mehta S.Q., Pichaud F., Bellen H.J., Quiocho F.A. Sec15 interacts with Rab11 via a novel domain and affects Rab11 localization in vivo. Nat Struct Mol Biol. 2005;12:879–885. doi: 10.1038/nsmb987. [DOI] [PubMed] [Google Scholar]
  128. Yoshimura S., Egerer J., Fuchs E., Haas A.K., Barr F.A. Functional dissection of Rab GTPases involved in primary cilium formation. J Cell Biol. 2007;178:363–369. doi: 10.1083/jcb.200703047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  129. Zaghloul N.A., Katsanis N. Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J Clin Invest. 2009;119:428–437. doi: 10.1172/JCI37041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  130. Zerial M., McBride H. Rab proteins as membrane organizers. Nat Rev Mol Cell Biol. 2001;2:107–117. doi: 10.1038/35052055. [DOI] [PubMed] [Google 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. HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol Cell. 2007;27:197–213. doi: 10.1016/j.molcel.2007.05.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  132. Zhang X.M., Ellis S., Sriratana A., Mitchell C.A., Rowe T. Sec15 is an effector for the Rab11 GTPase in mammalian cells. J Biol Chem. 2004;279:43027–43034. doi: 10.1074/jbc.M402264200. [DOI] [PubMed] [Google Scholar]
  133. Zheng Y. G protein control of microtubule assembly. Annu Rev Cell Dev Biol. 2004;20:867–894. doi: 10.1146/annurev.cellbio.20.012103.094648. [DOI] [PubMed] [Google Scholar]
  134. Zuo X., Guo W., Lipschutz J.H. The exocyst protein Sec10 is necessary for primary ciliogenesis and cystogenesis in vitro. Mol Biol Cell. 2009;20:2522–2529. doi: 10.1091/mbc.E08-07-0772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  135. Zhou C., Cunningham L., Marcus A.I., Li Y., Kahn R.A. Arl2 and Arl3 regulate different microtubule-dependent processes. Mol Biol Cell. 2006;17:2476–2487. doi: 10.1091/mbc.E05-10-0929. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Protein & Cell are provided here courtesy of Oxford University Press

RESOURCES