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Kinesin superfamily motor proteins and intracellular transport

Key Points

  • Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.

  • KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system.

  • The mechanisms by which different kinesins recognize, bind and unload specific cargo have been identified.

  • The spatiotemporal delivery of cargos by KIF-based transport can be regulated by phosphorylation, G proteins and Ca2+ levels.

  • It is now recognized that kinesins have unexpected roles in the regulation of physiological processes, such as higher brain function, tumour suppression and developmental patterning.

Abstract

Intracellular transport is fundamental for cellular function, survival and morphogenesis. Kinesin superfamily proteins (also known as KIFs) are important molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs. The mechanisms by which different kinesins recognize and bind to specific cargos, as well as how kinesins unload cargo and determine the direction of transport, have now been identified. Furthermore, recent molecular genetic experiments have uncovered important and unexpected roles for kinesins in the regulation of such physiological processes as higher brain function, tumour suppression and developmental patterning. These findings open exciting new areas of kinesin research.

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Figure 1: The structure and phylogeny of major mouse kinesins.
Figure 2: Intracellular transport by molecular motors in neurons, non-neuronal cells and cilia.
Figure 3: Kinesins, cargos and molecules involved in cargo recognition.
Figure 4: Regulation of kinesin–cargo binding by three different mechanisms.
Figure 5: The physiological relevance of kinesins in mice.

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References

  1. Hirokawa, N. Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 279, 519–526 (1998).

    CAS  PubMed  Google Scholar 

  2. Hirokawa, N. & Noda, Y. Intracellular transport and kinesin superfamily proteins, KIFs: structure, function, and dynamics. Physiol. Rev. 88, 1089–1118 (2008).

    CAS  PubMed  Google Scholar 

  3. Hirokawa, N. & Takemura, R. Molecular motors and mechanisms of directional transport in neurons. Nature Rev. Neurosci. 6, 201–214 (2005).

    CAS  Google Scholar 

  4. Vale, R. D. The molecular motor toolbox for intracellular transport. Cell 112, 467–480 (2003).

    CAS  PubMed  Google Scholar 

  5. Hirokawa, N. Cross-linker system between neurofilaments, microtubules, and membranous organelles in frog axons revealed by the quick-freeze, deep-etching method. J. Cell Biol. 94, 129–142 (1982). A pioneering paper that describes structural candidates of microtubule-based motor proteins in the axon.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Aizawa, H. et al. Kinesin family in murine central nervous system. J. Cell Biol. 119, 1287–1296 (1992). The first identification of kinesin superfamily proteins using molecular biology techniques.

    CAS  PubMed  Google Scholar 

  7. Miki, H., Setou, M., Kaneshiro, K. & Hirokawa, N. All kinesin superfamily protein, KIF, genes in mouse and human. Proc. Natl Acad. Sci. USA 98, 7004–7011 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Lawrence, C. J. et al. A standardized kinesin nomenclature. J. Cell Biol. 167, 19–22 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Dagenbach, E. M. & Endow, S. A. A new kinesin tree. J. Cell Sci. 117, 3–7 (2004).

    CAS  PubMed  Google Scholar 

  10. Terada, S. Where does slow axonal transport go? Neurosci. Res. 47, 367–372 (2003).

    CAS  PubMed  Google Scholar 

  11. Hall, D. H. & Hedgecock, E. M. Kinesin-related gene unc-104 is required for axonal transport of synaptic vesicles in C. elegans. Cell 65, 837–847 (1991).

    CAS  PubMed  Google Scholar 

  12. Okada, Y., Yamazaki, H., Sekine-Aizawa, Y. & Hirokawa, N. The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors. Cell 81, 769–780 (1995).

    CAS  PubMed  Google Scholar 

  13. Zhao, C. et al. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1B β. Cell 105, 587–597 (2001). A Kif1b heterozygote mouse was generated by gene targeting and found to be a good model of progressive peripheral neuropathies.

    CAS  PubMed  Google Scholar 

  14. Vale, R. D., Reese, T. S. & Sheetz, M. P. Identification of a novel force-generating protein, kinesin, involved in microtubule-based motility. Cell 42, 39–50 (1985). Identifies conventional kinesin (kinesin 1).

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Hirokawa, N. et al. Submolecular domains of bovine brain kinesin identified by electron microscopy and monoclonal antibody decoration. Cell 56, 867–878 (1989). Demonstrates the structure of kinesins using electron microscopy and reveals that kinesins are built from heavy chains and light chains.

    CAS  PubMed  Google Scholar 

  16. Yang, J. T., Laymon, R. A. & Goldstein, L. S. A three-domain structure of kinesin heavy chain revealed by DNA sequence and microtubule binding analyses. Cell 56, 879–889 (1989).

    CAS  PubMed  Google Scholar 

  17. Kanai, Y. et al. KIF5C, a novel neuronal kinesin enriched in motor neurons. J. Neurosci. 20, 6374–6384 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Gyoeva, F. K., Sarkisov, D. V., Khodjakov, A. L. & Minin, A. A. The tetrameric molecule of conventional kinesin contains identical light chains. Biochemistry 43, 13525–13531 (2004).

    CAS  PubMed  Google Scholar 

  19. Byrd, D. T. et al. UNC-16, a JNK-signaling scaffold protein, regulates vesicle transport in C. elegans. Neuron 32, 787–800 (2001).

    CAS  PubMed  Google Scholar 

  20. Toda, H. et al. UNC-51/ATG1 kinase regulates axonal transport by mediating motor-cargo assembly. Genes Dev. 22, 3292–3307 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Diefenbach, R. J., Diefenbach, E., Douglas, M. W. & Cunningham, A. L. The heavy chain of conventional kinesin interacts with the SNARE proteins SNAP25 and SNAP23. Biochemistry 41, 14906–14915 (2002).

    CAS  PubMed  Google Scholar 

  22. Su, Q., Cai, Q., Gerwin, C., Smith, C. L. & Sheng, Z. H. Syntabulin is a microtubule-associated protein implicated in syntaxin transport in neurons. Nature Cell Biol. 6, 941–953 (2004).

    CAS  PubMed  Google Scholar 

  23. Nangaku, M. et al. KIF1B, a novel microtubule plus end-directed monomeric motor protein for transport of mitochondria. Cell 79, 1209–1220 (1994).

    CAS  PubMed  Google Scholar 

  24. Wozniak, M. J., Melzer, M., Dorner, C., Haring, H. U. & Lammers, R. The novel protein KBP regulates mitochondria localization by interaction with a kinesin-like protein. BMC Cell Biol. 6, 35 (2005).

    PubMed Central  PubMed  Google Scholar 

  25. Tanaka, Y. et al. Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell 93, 1147–1158 (1998).

    CAS  PubMed  Google Scholar 

  26. Cai, Q., Gerwin, C. & Sheng, Z. H. Syntabulin-mediated anterograde transport of mitochondria along neuronal processes. J. Cell Biol. 170, 959–969 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Glater, E. E., Megeath, L. J., Stowers, R. S. & Schwarz, T. L. Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent. J. Cell Biol. 173, 545–557 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Cho, K. I. et al. Association of the kinesin-binding domain of RanBP2 to KIF5B and KIF5C determines mitochondria localization and function. Traffic 8, 1722–1735 (2007).

    CAS  PubMed  Google Scholar 

  29. Wang, X. & Schwarz, T. L. The mechanism of Ca2+-dependent regulation of kinesin-mediated mitochondrial motility. Cell 136, 163–174 (2009). Clarifies the molecular mechanism of the Ca2+-dependent regulation of mitochondrial transport.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Cole, D. G. et al. Novel heterotrimeric kinesin-related protein purified from sea urchin eggs. Nature 366, 268–270 (1993).

    CAS  PubMed  Google Scholar 

  31. Kondo, S. et al. KIF3A is a new microtubule-based anterograde motor in the nerve axon. J. Cell Biol. 125, 1095–1107 (1994).

    CAS  PubMed  Google Scholar 

  32. Yamazaki, H., Nakata, T., Okada, Y. & Hirokawa, N. KIF3A/B: a heterodimeric kinesin superfamily protein that works as a microtubule plus end-directed motor for membrane organelle transport. J. Cell Biol. 130, 1387–1399 (1995).

    CAS  PubMed  Google Scholar 

  33. Wedaman, K. P., Meyer, D. W., Rashid, D. J., Cole, D. G. & Scholey, J. M. Sequence and submolecular localization of the 115-kD accessory subunit of the heterotrimeric kinesin-II (KRP85/95) complex. J. Cell Biol. 132, 371–380 (1996).

    CAS  PubMed  Google Scholar 

  34. Yamazaki, H., Nakata, T., Okada, Y. & Hirokawa, N. Cloning and characterization of KAP3: a novel kinesin superfamily-associated protein of KIF3A/3B. Proc. Natl Acad. Sci. USA 93, 8443–8448 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hirokawa, N. Stirring up development with the heterotrimeric kinesin KIF3. Traffic 1, 29–34 (2000).

    CAS  PubMed  Google Scholar 

  36. Takeda, S. et al. Kinesin superfamily protein 3 (KIF3) motor transports fodrin-associating vesicles important for neurite building. J. Cell Biol. 148, 1255–1265 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Taya, S. et al. DISC1 regulates the transport of the NUDEL/LIS1/14-3-3ɛ complex through kinesin-1. J. Neurosci. 27, 15–26 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Baas, P. W., Deitch, J. S., Black, M. M. & Banker, G. A. Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite. Proc. Natl Acad. Sci. USA 85, 8335–8339 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Nakata, T. & Hirokawa, N. Microtubules provide directional cues for polarized axonal transport through interaction with kinesin motor head. J. Cell Biol. 162, 1045–1055 (2003). The first description of how the KIF5 motor domain preferentially localizes to the axon. It also shows the importance of microtubule dynamics in this process.

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Jacobson, C., Schnapp, B. & Banker, G. A. A change in the selective translocation of the kinesin-1 motor domain marks the initial specification of the axon. Neuron 49, 797–804 (2006).

    CAS  PubMed  Google Scholar 

  41. Witte, H., Neukirchen, D. & Bradke, F. Microtubule stabilization specifies initial neuronal polarization. J. Cell Biol. 180, 619–632 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Shi, S. H., Cheng, T., Jan, L. Y. & Jan, Y. N. APC and GSK-3β are involved in mPar3 targeting to the nascent axon and establishment of neuronal polarity. Curr. Biol. 14, 2025–2032 (2004).

    CAS  PubMed  Google Scholar 

  43. Nishimura, T. et al. Role of the PAR-3–KIF3 complex in the establishment of neuronal polarity. Nature Cell Biol. 6, 328–334 (2004).

    CAS  PubMed  Google Scholar 

  44. Hanada, T., Lin, L., Tibaldi, E. V., Reinherz, E. L. & Chishti, A. H. GAKIN, a novel kinesin-like protein associates with the human homologue of the Drosophila discs large tumor suppressor in T lymphocytes. J. Biol. Chem. 275, 28774–28784 (2000).

    CAS  PubMed  Google Scholar 

  45. Siegrist, S. E. & Doe, C. Q. Microtubule-induced Pins/Gαi cortical polarity in Drosophila neuroblasts. Cell 123, 1323–1335 (2005).

    CAS  PubMed  Google Scholar 

  46. Venkateswarlu, K., Hanada, T. & Chishti, A. H. Centaurin-α1 interacts directly with kinesin motor protein KIF13B. J. Cell Sci. 118, 2471–2484 (2005).

    CAS  PubMed  Google Scholar 

  47. Horiguchi, K., Hanada, T., Fukui, Y. & Chishti, A. H. Transport of PIP3 by GAKIN, a kinesin-3 family protein, regulates neuronal cell polarity. J. Cell Biol. 174, 425–436 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Diefenbach, R. J., Mackay, J. P., Armati, P. J. & Cunningham, A. L. The C-terminal region of the stalk domain of ubiquitous human kinesin heavy chain contains the binding site for kinesin light chain. Biochemistry 37, 16663–16670 (1998).

    CAS  PubMed  Google Scholar 

  49. Skoufias, D. A., Cole, D. G., Wedaman, K. P. & Scholey, J. M. The carboxyl-terminal domain of kinesin heavy chain is important for membrane binding. J. Biol. Chem. 269, 1477–1485 (1994).

    CAS  PubMed  Google Scholar 

  50. Seiler, S. et al. Cargo binding and regulatory sites in the tail of fungal conventional kinesin. Nature Cell Biol. 2, 333–338 (2000).

    CAS  PubMed  Google Scholar 

  51. Bowman, A. B. et al. Kinesin-dependent axonal transport is mediated by the sunday driver (SYD) protein. Cell 103, 583–594 (2000).

    CAS  PubMed  Google Scholar 

  52. Verhey, K. J. et al. Cargo of kinesin identified as JIP scaffolding proteins and associated signaling molecules. J. Cell Biol. 152, 959–970 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Hammond, J. W., Griffin, K., Jih, G. T., Stuckey, J. & Verhey, K. J. Co-operative versus independent transport of different cargoes by Kinesin-1. Traffic 9, 725–741 (2008).

    CAS  PubMed  Google Scholar 

  54. Kelkar, N., Gupta, S., Dickens, M. & Davis, R. J. Interaction of a mitogen-activated protein kinase signaling module with the neuronal protein JIP3. Mol. Cell. Biol. 20, 1030–1043 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Kamal, A., Stokin, G. B., Yang, Z., Xia, C. H. & Goldstein, L. S. Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron 28, 449–459 (2000).

    CAS  PubMed  Google Scholar 

  56. Lazarov, O. et al. Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: revisited. J. Neurosci. 25, 2386–2395 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Inomata, H. et al. A scaffold protein JIP-1b enhances amyloid precursor protein phosphorylation by JNK and its association with kinesin light chain 1. J. Biol. Chem. 278, 22946–22955 (2003).

    CAS  PubMed  Google Scholar 

  58. Terada, S., Kinjo, M. & Hirokawa, N. Oligomeric tubulin in large transporting complex is transported via kinesin in squid giant axons. Cell 103, 141–155 (2000).

    CAS  PubMed  Google Scholar 

  59. Kimura, T., Watanabe, H., Iwamatsu, A. & Kaibuchi, K. Tubulin and CRMP-2 complex is transported via kinesin-1. J. Neurochem. 93, 1371–1382 (2005).

    CAS  PubMed  Google Scholar 

  60. Xia, C. H. et al. Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A. J. Cell Biol. 161, 55–66 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Kanai, Y., Dohmae, N. & Hirokawa, N. Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43, 513–525 (2004). Identifies 42 components of the large RNA-transporting granule that is transported by KIF5 motors.

    CAS  PubMed  Google Scholar 

  62. Dictenberg, J. B., Swanger, S. A., Antar, L. N., Singer, R. H. & Bassell, G. J. A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome. Dev. Cell 14, 926–939 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Setou, M. et al. Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites. Nature 417, 83–87 (2002).

    CAS  PubMed  Google Scholar 

  64. Nakagawa, T. et al. Identification and classification of 16 new kinesin superfamily (KIF) proteins in mouse genome. Proc. Natl Acad. Sci. USA 94, 9654–9659 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Setou, M., Nakagawa, T., Seog, D. H. & Hirokawa, N. Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science 288, 1796–1802 (2000). Shows that KIF17 transports NR2B-containing vesicles through the scaffolding protein complex that consists of LIN10, LIN2 and LIN7 in dendrites.

    CAS  PubMed  Google Scholar 

  66. Jo, K., Derin, R., Li, M. & Bredt, D. S. Characterization of MALS/Velis-1, -2, and -3: a family of mammalian LIN-7 homologs enriched at brain synapses in association with the postsynaptic density-95/NMDA receptor postsynaptic complex. J. Neurosci. 19, 4189–4199 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Kayadjanian, N., Lee, H. S., Pina-Crespo, J. & Heinemann, S. F. Localization of glutamate receptors to distal dendrites depends on subunit composition and the kinesin motor protein KIF17. Mol. Cell. Neurosci. 34, 219–230 (2007).

    CAS  PubMed  Google Scholar 

  68. Chu, P. J., Rivera, J. F. & Arnold, D. B. A role for Kif17 in transport of Kv4. 2. J. Biol. Chem. 281, 365–373 (2006).

    CAS  PubMed  Google Scholar 

  69. Hanlon, D. W., Yang, Z. & Goldstein, L. S. Characterization of KIFC2, a neuronal kinesin superfamily member in mouse. Neuron 18, 439–451 (1997).

    CAS  PubMed  Google Scholar 

  70. Saito, N. et al. KIFC2 is a novel neuron-specific C-terminal type kinesin superfamily motor for dendritic transport of multivesicular body-like organelles. Neuron 18, 425–438 (1997).

    CAS  PubMed  Google Scholar 

  71. Santama, N., Er, C. P., Ong, L. L. & Yu, H. Distribution and functions of kinectin isoforms. J. Cell Sci. 117, 4537–4549 (2004).

    CAS  PubMed  Google Scholar 

  72. Plitz, T. & Pfeffer, K. Intact lysosome transport and phagosome function despite kinectin deficiency. Mol. Cell. Biol. 21, 6044–6055 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Wozniak, M. J. & Allan, V. J. Cargo selection by specific kinesin light chain 1 isoforms. EMBO J. 25, 5457–5468 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Stauber, T., Simpson, J. C., Pepperkok, R. & Vernos, I. A role for kinesin-2 in COPI-dependent recycling between the ER and the Golgi complex. Curr. Biol. 16, 2245–2251 (2006).

    CAS  PubMed  Google Scholar 

  75. Echard, A. et al. Interaction of a Golgi-associated kinesin-like protein with Rab6. Science 279, 580–585 (1998).

    CAS  PubMed  Google Scholar 

  76. Harada, A. et al. Golgi vesiculation and lysosome dispersion in cells lacking cytoplasmic dynein. J. Cell Biol. 141, 51–59 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Xu, Y. et al. Role of KIFC3 motor protein in Golgi positioning and integration. J. Cell Biol. 158, 293–303 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Nakagawa, T. et al. A novel motor, KIF13A, transports mannose-6-phosphate receptor to plasma membrane through direct interaction with AP-1 complex. Cell 103, 569–581 (2000). Shows that KIF13A transports mannose-6-phosphate receptor from the TGN to the plasma membrane through β1-adaptin.

    CAS  PubMed  Google Scholar 

  79. Lippincott-Schwartz, J., Cole, N. B., Marotta, A., Conrad, P. A. & Bloom, G. S. Kinesin is the motor for microtubule-mediated Golgi-to-ER membrane traffic. J. Cell Biol. 128, 293–306 (1995).

    CAS  PubMed  Google Scholar 

  80. Noda, Y. et al. KIFC3, a microtubule minus end-directed motor for the apical transport of annexin XIIIb-associated triton-insoluble membranes. J. Cell Biol. 155, 77–88 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Meng, W., Mushika, Y., Ichii, T. & Takeichi, M. Anchorage of microtubule minus ends to adherens junctions regulates epithelial cell–cell contacts. Cell 135, 948–959 (2008). Shows that PLEKHA7 and nezha anchor microtubule minus ends to apical zonula adherens in epithelial cells and recruit KIFC3 to stabilize apical zonula adherens.

    CAS  PubMed  Google Scholar 

  82. Jaulin, F., Xue, X., Rodriguez-Boulan, E. & Kreitzer, G. Polarization-dependent selective transport to the apical membrane by KIF5B in MDCK cells. Dev. Cell 13, 511–522 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Nakata, T. & Hirokawa, N. Point mutation of adenosine triphosphate-binding motif generated rigor kinesin that selectively blocks anterograde lysosome membrane transport. J. Cell Biol. 131, 1039–1053 (1995).

    CAS  PubMed  Google Scholar 

  84. Gross, S. P., Welte, M. A., Block, S. M. & Wieschaus, E. F. Coordination of opposite-polarity microtubule motors. J. Cell Biol. 156, 715–724 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Jordens, I., Marsman, M., Kuijl, C. & Neefjes, J. Rab proteins, connecting transport and vesicle fusion. Traffic 6, 1070–1077 (2005).

    CAS  PubMed  Google Scholar 

  86. Bananis, E., Murray, J. W., Stockert, R. J., Satir, P. & Wolkoff, A. W. Microtubule and motor-dependent endocytic vesicle sorting in vitro. J. Cell Biol. 151, 179–186 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Imamura, T. et al. Insulin-induced GLUT4 translocation involves protein kinase C-λ-mediated functional coupling between Rab4 and the motor protein kinesin. Mol. Cell. Biol. 23, 4892–4900 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Bananis, E. et al. Microtubule-dependent movement of late endocytic vesicles in vitro: requirements for dynein and kinesin. Mol. Biol. Cell 15, 3688–3697 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Brown, C. L. et al. Kinesin-2 is a motor for late endosomes and lysosomes. Traffic 6, 1114–1124 (2005).

    CAS  PubMed  Google Scholar 

  90. Schonteich, E. et al. The Rip11/Rab11-FIP5 and kinesin II complex regulates endocytic protein recycling. J. Cell Sci. 121, 3824–3833 (2008).

    CAS  PubMed  Google Scholar 

  91. Hoepfner, S. et al. Modulation of receptor recycling and degradation by the endosomal kinesin KIF16B. Cell 121, 437–450 (2005). Shows that KIF16B binds to PtdIns(3,4,5)P 3 -containing endosomes and fixes EGFs and EGF receptors beneath the plasma membrane through its plus end-directed motility.

    CAS  PubMed  Google Scholar 

  92. Kozminski, K. G., Johnson, K. A., Forscher, P. & Rosenbaum, J. L. A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc. Natl Acad. Sci. USA 90, 5519–5523 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Cole, D. G. et al. Chlamydomonas kinesin-II-dependent intraflagellar transport (IFT): IFT particles contain proteins required for ciliary assembly in Caenorhabditis elegans sensory neurons. J. Cell Biol. 141, 993–1008 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Ou, G., Blacque, O. E., Snow, J. J., Leroux, M. R. & Scholey, J. M. Functional coordination of intraflagellar transport motors. Nature 436, 583–587 (2005). Reveals that kinesin 2 and OSM3 work partially synergistically for the transport of particle complexes to the tips of flagella.

    CAS  PubMed  Google Scholar 

  95. Jenkins, P. M. et al. Ciliary targeting of olfactory CNG channels requires the CNGB1b subunit and the kinesin-2 motor protein, KIF17. Curr. Biol. 16, 1211–1216 (2006).

    CAS  PubMed  Google Scholar 

  96. Dietrich, K. A. et al. The kinesin-1 motor protein is regulated by a direct interaction of its head and tail. Proc. Natl Acad. Sci. USA 105, 8938–8943 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Wong, Y. L., Dietrich, K. A., Naber, N., Cooke, R. & Rice, S. E. The kinesin-1 tail conformationally restricts the nucleotide pocket. Biophys. J. 96, 2799–2807 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Hammond, J. W. et al. Mammalian kinesin-3 motors are dimeric in vivo and move by processive motility upon release of autoinhibition. PLoS Biol. 7, e72 (2009).

    PubMed  Google Scholar 

  99. Sato-Yoshitake, R., Yorifuji, H., Inagaki, M. & Hirokawa, N. The phosphorylation of kinesin regulates its binding to synaptic vesicles. J. Biol. Chem. 267, 23930–23936 (1992).

    CAS  PubMed  Google Scholar 

  100. Hollenbeck, P. J. Phosphorylation of neuronal kinesin heavy and light chains in vivo. J. Neurochem. 60, 2265–2275 (1993).

    CAS  PubMed  Google Scholar 

  101. Morfini, G., Szebenyi, G., Elluru, R., Ratner, N. & Brady, S. T. Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J. 21, 281–293 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Guillaud, L., Wong, R. & Hirokawa, N. Disruption of KIF17–Mint1 interaction by CaMKII-dependent phosphorylation: a molecular model of kinesin-cargo release. Nature Cell Biol. 10, 19–29 (2008). Shows that CaMKII-dependent phosphorylation of the cargo-binding domain of KIF17 causes unloading of NR2B-carrying vesicles.

    CAS  PubMed  Google Scholar 

  103. Morfini, G. et al. JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. Nature Neurosci. 9, 907–916 (2006).

    CAS  PubMed  Google Scholar 

  104. Stagi, M., Gorlovoy, P., Larionov, S., Takahashi, K. & Neumann, H. Unloading kinesin transported cargoes from the tubulin track via the inflammatory c-Jun N-terminal kinase pathway. FASEB J. 20, 2573–2575 (2006).

    CAS  PubMed  Google Scholar 

  105. Horiuchi, D. et al. Control of a kinesin–cargo linkage mechanism by JNK pathway kinases. Curr. Biol. 17, 1313–1317 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Gindhart, J. G. et al. The kinesin-associated protein UNC-76 is required for axonal transport in the Drosophila nervous system. Mol. Biol. Cell 14, 3356–3365 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Ogura, K. et al. Caenorhabditis elegans unc-51 gene required for axonal elongation encodes a novel serine/threonine kinase. Genes Dev. 8, 2389–2400 (1994).

    CAS  PubMed  Google Scholar 

  108. Midorikawa, R., Takei, Y. & Hirokawa, N. KIF4 motor regulates activity-dependent neuronal survival by suppressing PARP-1 enzymatic activity. Cell 125, 371–383 (2006). Functional analysis of Kif4 - knockout neurons reveals a role for KIF4 in activity-dependent neuronal survival.

    CAS  PubMed  Google Scholar 

  109. Zerial, M. & McBride, H. Rab proteins as membrane organizers. Nature Rev. Mol. Cell Biol. 2, 107–117 (2001).

    CAS  Google Scholar 

  110. Goud, B., Zahraoui, A., Tavitian, A. & Saraste, J. Small GTP-binding protein associated with Golgi cisternae. Nature 345, 553–556 (1990).

    CAS  PubMed  Google Scholar 

  111. Hill, E., Clarke, M. & Barr, F. A. The Rab6-binding kinesin, Rab6-KIFL, is required for cytokinesis. EMBO J. 19, 5711–5719 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Fontijn, R. D. et al. The human kinesin-like protein RB6K is under tight cell cycle control and is essential for cytokinesis. Mol. Cell. Biol. 21, 2944–2955 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Chavrier, P., Parton, R. G., Hauri, H. P., Simons, K. & Zerial, M. Localization of low molecular weight GTP binding proteins to exocytic and endocytic compartments. Cell 62, 317–329 (1990).

    CAS  PubMed  Google Scholar 

  114. Nielsen, E., Severin, F., Backer, J. M., Hyman, A. A. & Zerial, M. Rab5 regulates motility of early endosomes on microtubules. Nature Cell Biol. 1, 376–382 (1999).

    CAS  PubMed  Google Scholar 

  115. Niwa, S., Tanaka, Y. & Hirokawa, N. KIF1Bβ- and KIF1A-mediated axonal transport of presynaptic regulator Rab3 occurs in a GTP-dependent manner through DENN/MADD. Nature Cell Biol. 10, 1269–1279 (2008). The binding of GTP-bound RAB3 to KIF1Bβ and KIF1A through DENN/MADD was shown to be required for the transport of RAB3-carrying vesicles.

    CAS  PubMed  Google Scholar 

  116. Klopfenstein, D. R., Tomishige, M., Stuurman, N. & Vale, R. D. Role of phosphatidylinositol(4,5) bisphosphate organization in membrane transport by the Unc104 kinesin motor. Cell 109, 347–358 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Klopfenstein, D. R. & Vale, R. D. The lipid binding pleckstrin homology domain in UNC-104 kinesin is necessary for synaptic vesicle transport in Caenorhabditis elegans. Mol. Biol. Cell 15, 3729–3739 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  118. De Robertis, E. D. & Bennett, H. S. Some features of the submicroscopic morphology of synapses in frog and earthworm. J. Biophys. Biochem. Cytol. 1, 47–58 (1955).

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Rintoul, G. L., Filiano, A. J., Brocard, J. B., Kress, G. J. & Reynolds, I. J. Glutamate decreases mitochondrial size and movement in primary forebrain neurons. J. Neurosci. 23, 7881–7888 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Yi, M., Weaver, D. & Hajnoczky, G. Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit. J. Cell Biol. 167, 661–672 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Hollenbeck, P. J. & Saxton, W. M. The axonal transport of mitochondria. J. Cell Sci. 118, 5411–5419 (2005).

    CAS  PubMed  Google Scholar 

  122. Chang, D. T., Honick, A. S. & Reynolds, I. J. Mitochondrial trafficking to synapses in cultured primary cortical neurons. J. Neurosci. 26, 7035–7045 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Stowers, R. S., Megeath, L. J., Górska-Andrzejak, J., Meinertzhagen, I. A. & Schwarz, T. L. Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein. Neuron 36, 1063–1077 (2002).

    CAS  PubMed  Google Scholar 

  124. Guo, X. et al. The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses. Neuron 47, 379–393 (2005).

    CAS  PubMed  Google Scholar 

  125. Macaskill, A. F. et al. Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. Neuron 61, 541–555 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Nonaka, S. et al. 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 (1998). The first paper to propose the nodal-flow hypothesis of left–right determination in the Kif3b - knockout mouse.

    CAS  PubMed  Google Scholar 

  127. Yonekawa, Y. et al. Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice. J. Cell Biol. 141, 431–441 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Takeda, S. et al. Left–right asymmetry and kinesin superfamily protein KIF3A: new insights in determination of laterality and mesoderm induction by kif3A−/− mice analysis. J. Cell Biol. 145, 825–836 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Marszalek, J. R., Ruiz-Lozano, P., Roberts, E., Chien, K. R. & Goldstein, L. S. Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II. Proc. Natl Acad. Sci. USA 96, 5043–5048 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Marszalek, J. R. et al. Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptors. Cell 102, 175–187 (2000).

    CAS  PubMed  Google Scholar 

  131. Wong, R. W., Setou, M., Teng, J., Takei, Y. & Hirokawa, N. Overexpression of motor protein KIF17 enhances spatial and working memory in transgenic mice. Proc. Natl Acad. Sci. USA 99, 14500–14505 (2002). The Kif17 -transgenic mouse revealed the in vivo role of KIF17 in the enhancement of learning and memory.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Homma, N. et al. Kinesin superfamily protein 2A (KIF2A) functions in suppression of collateral branch extension. Cell 114, 229–239 (2003).

    CAS  PubMed  Google Scholar 

  133. Lin, F. et al. Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc. Natl Acad. Sci. USA 100, 5286–5291 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Teng, J. et al. The KIF3 motor transports N-cadherin and organizes the developing neuroepithelium. Nature Cell Biol. 7, 474–482 (2005). Analysis of Kap3 conditional knockout mice suggests a signal transduction cascade is modulated by the KIF-mediated transport of signalling molecules, and that KIF3 suppresses tumorigenesis.

    CAS  PubMed  Google Scholar 

  135. Kolpakova-Hart, E., Jinnin, M., Hou, B., Fukai, N. & Olsen, B. R. Kinesin-2 controls development and patterning of the vertebrate skeleton by Hedgehog- and Gli3-dependent mechanisms. Dev. Biol. 309, 273–284 (2007).

    CAS  PubMed  Google Scholar 

  136. Koyama, E. et al. Conditional Kif3a ablation causes abnormal hedgehog signaling topography, growth plate dysfunction, and excessive bone and cartilage formation during mouse skeletogenesis. Development 134, 2159–2169 (2007).

    CAS  PubMed  Google Scholar 

  137. Haycraft, C. J. et al. Intraflagellar transport is essential for endochondral bone formation. Development 134, 307–316 (2007).

    CAS  PubMed  Google Scholar 

  138. Davenport, J. R. et al. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr. Biol. 17, 1586–1594 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Okada, Y. et al. Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol. Cell 4, 459–468 (1999).

    CAS  PubMed  Google Scholar 

  140. Tanaka, Y., Okada, Y. & Hirokawa, N. FGF-induced vesicular release of sonic hedgehog and retinoic acid in leftward nodal flow is critical for left–right determination. Nature 435, 172–177 (2005).

    CAS  PubMed  Google Scholar 

  141. Okada, Y., Takeda, S., Tanaka, Y., Belmonte, J. C. & Hirokawa, N. Mechanism of nodal flow: a conserved symmetry breaking event in left–right axis determination. Cell 121, 633–644 (2005).

    CAS  PubMed  Google Scholar 

  142. Hirokawa, N., Tanaka, Y., Okada, Y. & Takeda, S. Nodal flow and the generation of left-right asymmetry. Cell 125, 33–45 (2006).

    CAS  PubMed  Google Scholar 

  143. Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83–87 (2003).

    CAS  PubMed  Google Scholar 

  144. Chevalier-Larsen, E. & Holzbaur, E. L. Axonal transport and neurodegenerative disease. Biochim. Biophys. Acta 1762, 1094–1108 (2006).

    CAS  PubMed  Google Scholar 

  145. Reid, E. et al. A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am. J. Hum. Genet. 71, 1189–1194 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Marszalek, J. R., Weiner, J. A., Farlow, S. J., Chun, J. & Goldstein, L. S. Novel dendritic kinesin sorting identified by different process targeting of two related kinesins: KIF21A and KIF21B. J. Cell Biol. 145, 469–479 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Yamada, K. et al. Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nature Genet. 35, 318–321 (2003).

    CAS  PubMed  Google Scholar 

  148. Shen, X. et al. Interaction of brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 and kinesin motor protein KIF21A. Proc. Natl Acad. Sci. USA 105, 18788–18793 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Sekine, Y. et al. A novel microtubule-based motor protein (KIF4) for organelle transports, whose expression is regulated developmentally. J. Cell Biol. 127, 187–201 (1994).

    CAS  PubMed  Google Scholar 

  150. Peretti, D., Peris, L., Rosso, S., Quiroga, S. & Cáceres, A. Evidence for the involvement of KIF4 in the anterograde transport of L1-containing vesicles. J. Cell Biol. 149, 141–152 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Puthanveettil, S. V. et al. A new component in synaptic plasticity: upregulation of kinesin in the neurons of the gill-withdrawal reflex. Cell 135, 960–973 (2008). Analyses the role of KIF5 in the A. mollusca gill withdrawal reflex.

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Lawrence, C. J., Malmberg, R. L., Muszynski, M. G. & Dawe, R. K. Maximum likelihood methods reveal conservation of function among closely related kinesin families. J. Mol. Evol. 54, 42–53 (2002).

    CAS  PubMed  Google Scholar 

  153. Miki, H., Setou, M., Hirokawa, N., Group, R. G. & Members, G. Kinesin superfamily proteins (KIFs) in the mouse transcriptome. Genome Res. 13, 1455–1465 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Miki, H., Okada, Y. & Hirokawa, N. Analysis of the kinesin superfamily: insights into structure and function. Trends Cell Biol. 15, 467–476 (2005).

    CAS  PubMed  Google Scholar 

  155. Hirokawa, N., Okada, Y. & Tanaka, Y. Fluid dynamic mechanism responsible for breaking the left–right symmetry of the human body: the nodal flow. Ann. Rev. Fluid Mech. 41, 53–72 (2009).

    Google Scholar 

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Acknowledgements

The authors thank H. Fukuda, H. Sato and all other members of the Hirokawa laboratory for their technical assistance, support and discussion. This work was supported by a Grant-in-Aid for Specially Promoted Research to N. H. and a global COE programme to the University of Tokyo from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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DATABASES

OMIM

CFEOM1

Joubert syndrome

Kartagener syndrome

polycystic kidney

spinal and bulbar muscular atrophy

FURTHER INFORMATION

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Glossary

WD40 repeat

A protein motif that is composed of a 40 amino acid repeat that forms a blade of the characteristic β-propeller structure. Proteins that contain WD40 repeats participate in G protein-mediated signal transduction, transcriptional regulation, RNA processing and regulation of vesicle formation and trafficking.

Synaptophysin

A glycoprotein of 38 kDa that is localized to synaptic vesicle membranes.

Synaptotagmin

One of a group of Ca2+-binding proteins that are involved in the secretion of granules and vesicles, especially in the nervous system.

Haploinsufficiency

Occurs when a diploid organism has only a single functional copy of a gene that does not produce enough of a gene product to bring about a wild-type condition. This leads to an abnormal or diseased state.

Synaptobrevin

An integral synaptic vesicle protein of 18 kDa that is involved in the formation of the SNARE complex in exocytosis. Synaptobrevin is a major target of cleavage by tetanus toxin.

Armadillo repeat

A protein–protein interaction consensus stretch of 40 amino acids.

Tetratricopeptide motif

A loosely conserved domain of 30–40 amino acids that is involved in protein–protein interactions.

Voltage-gated potassium channel

A class of transmembrane channel that senses the electrical potential across the plasma membrane to open and admit K+ flow through the membrane.

Apical transport

A mode of organelle transport in polarized cells towards the apical surface of the cell.

Zonula adherens

A cell–cell adherens junction that forms a circumferential belt around the apical pole of epithelial cells.

Melanosome

An organelle that contains melanin, a common light-absorbing pigment.

Endomembrane

An intracellular lipid bilayer membrane that surrounds small spaces, for example to form vesicles and membrane organelles. Endomembranes fuse with and are removed from the plasma membrane by exocytosis and endocytosis, respectively.

PX domain

(Phox homology domain). A lipid and protein interaction domain that consists of 100–130 amino acids and is defined by sequences that are found in two components of the phagocyte NADPH oxidase (phox) complex.

Pleckstrin homology (PH) domain

A sequence of 100 amino acids that is present in many signalling molecules and binds to lipid products of phosphoinositide kinases.

EF hand

A protein motif that might bind to Ca2+.

Planar cell polarity

A one-dimensional polarity on a cell sheet that is essential for many aspects of the development of tissues.

Hereditary spastic paraplegia

A human progressive neuronal disease of hereditary origin that is characterized by increasing weakness and stiffness of the legs.

Laminary defect

A developmental defect of the brain that disorganizes the laminary structure of the cortex.

Long-term facilitation

A mode of synaptic plasticity in which stimulation results in a persistent increase in synaptic transmission.

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Hirokawa, N., Noda, Y., Tanaka, Y. et al. Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol 10, 682–696 (2009). https://doi.org/10.1038/nrm2774

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