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Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites

Nature volume 417, pages 83–87 (2002)Cite this article

Abstract

In cells, molecular motors operate in polarized sorting of molecules, although the steering mechanisms of motors remain elusive1. In neurons, the kinesin motor2 conducts vesicular transport such as the transport of synaptic vesicle components to axons3 and of neurotransmitter receptors to dendrites4, indicating that vesicles may have to drive the motor for the direction to be correct. Here we show that an AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionate) receptor subunit—GluR2-interacting protein (GRIP1)—can directly interact and steer kinesin heavy chains to dendrites as a motor for AMPA receptors. As would be expected if this complex is functional, both gene targeting and dominant negative experiments of heavy chains of mouse kinesin showed abnormal localization of GRIP1. Moreover, expression of the kinesin-binding domain of GRIP1 resulted in accumulation of the endogenous kinesin predominantly in the somatodendritic area. This pattern was different from that generated by the overexpression of the kinesin-binding scaffold protein JSAP1 (JNK/SAPK-associated protein-1, also known as Mapk8ip3), which occurred predominantly in the somatoaxon area. These results indicate that directly binding proteins can determine the traffic direction of a motor protein.

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Figure 1: Kinesin binds to GRIP1, and is necessary for normal localization of GRIP1.
Figure 2: Kinesin–GRIP1–GluR2 complex in vivo.
Figure 3: KHCCBD relocates GRIP1 and GluR2.
Figure 4: The GRIP1 kinesin-binding site recruits kinesin to the soma and dendrites.

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References

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

    Article  ADS  CAS  Google Scholar 

  2. 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)

    Article  CAS  Google Scholar 

  3. Ferreira, A., Niclas, J., Vale, R. D., Banker, G. & Kosik, K. S. Suppression of kinesin expression in cultured hippocampal neurons using antisense oligonucleotides. J. Cell Biol. 117, 595–606 (1992)

    Article  CAS  Google Scholar 

  4. Kim, C. H. & Lisman, J. E. A labile component of AMPA receptor-mediated synaptic transmission is dependent on microtubule motors, actin, and N-ethylmaleimide-sensitive factor. J. Neurosci. 21, 4188–4194 (2001)

    Article  CAS  Google Scholar 

  5. Burack, M. A., Silverman, M. A. & Banker, G. The role of selective transport in neuronal protein sorting. Neuron 26, 465–472 (2000)

    Article  CAS  Google Scholar 

  6. Severt, W. L. et al. The suppression of testis-brain RNA binding protein and kinesin heavy chain disrupts mRNA sorting in dendrites. J. Cell Sci. 112, 3691–3702 (1999)

    CAS  PubMed  Google Scholar 

  7. 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)

    Article  ADS  CAS  Google Scholar 

  8. Dong, H. et al. GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors. Nature 386, 279–284 (1997)

    Article  ADS  CAS  Google Scholar 

  9. Wyszynski, M. et al. Association of AMPA receptors with a subset of glutamate receptor-interacting protein in vivo. J. Neurosci. 19, 6528–6537 (1999)

    Article  CAS  Google Scholar 

  10. 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 

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

    Article  CAS  Google Scholar 

  12. 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)

    Article  CAS  Google Scholar 

  13. Bruckner, K. et al. EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains. Neuron 22, 511–524 (1999)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Rahman, A., Kamal, A., Roberts, E. A. & Goldstein, L. S. Defective kinesin heavy chain behaviour in mouse kinesin light chain mutants. J. Cell Biol. 146, 1277–1288 (1999)

    Article  CAS  Google Scholar 

  16. Rubio, M. E. & Wenthold, R. J. Differential distribution of intracellular glutamate receptors in dendrites. J. Neurosci. 19, 5549–5562 (1999)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Lee, S. H., Valtschanoff, J. G., Kharazia, V. N., Weinberg, R. & Sheng, M. Biochemical and morphological characterization of an intracellular membrane compartment containing AMPA receptors. Neuropharmacology 41, 680–692 (2001)

    Article  CAS  Google Scholar 

  19. Ye, B. et al. GRASP-1: a neuronal RasGEF associated with the AMPA receptor/GRIP complex. Neuron 26, 603–617 (2000)

    Article  CAS  Google Scholar 

  20. Ito, M. et al. JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signalling pathway. Mol. Cell. Biol. 19, 7539–7548 (1999)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. 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)

    Article  ADS  CAS  Google Scholar 

  23. Niclas, J., Navone, F., Hom-Booher, N. & Vale, R. D. Cloning and localization of a conventional kinesin motor expressed exclusively in neurons. Neuron 12, 1059–1072 (1994)

    Article  CAS  Google Scholar 

  24. 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)

    Article  CAS  Google Scholar 

  25. Toyoshima, I., Yu, H., Steuer, E. R. & Sheetz, M. P. Kinectin, a major kinesin-binding protein on ER. J. Cell Biol. 118, 1121–1131 (1992)

    Article  CAS  Google Scholar 

  26. Huang, J. D. et al. Direct interaction of microtubule- and actin-based transport motors. Nature 397, 267–270 (1999)

    Article  ADS  CAS  Google Scholar 

  27. 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 (2001)

    Article  Google Scholar 

  28. Burette, A. et al. Differential cellular and subcellular localization of AMPA receptor-binding protein and glutamate receptor-interacting protein. J. Neurosci. 21, 495–503 (2001)

    Article  CAS  Google Scholar 

  29. Brewer, G. J. Serum-free B27/neurobasal medium supports differentiated growth of neurons from the striatum, substantia nigra, septum, cerebral cortex, cerebellum, and dentate gyrus. J. Neurosci. Res. 42, 674–683 (1995)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. L. Huganir for the anti-GRIP1 and anti-GRIP2 antibodies, M. Mishina for anti-NR2B antibody, and M. Sheng for an anti-PanGRIP antibody. We thank Y. Hayashi for advice and for the Sindbis virus construction. We also thank Y. Hata, T. Nakagawa and M. Sheng for discussions; and H. Sato, H. Fukuda, T. Matsuki and M. Sugaya for technical assistance. Finally, we thank other members of the Hirokawa laboratory, especially T. Nakata, for technical assistance, discussions, and advice throughout the conducting of experiments. This work is supported by a Center of Excellence Grant-in-Aid from the Ministry of Education, Science, Sports, Culture and Technology of Japan to N. Hirokawa.

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Authors and Affiliations

  1. Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Tokyo, Bunkyo-ku, 113-0033, Japan

    Mitsutoshi Setou, Dae-Hyung Seog, Yosuke Tanaka, Yoshimitsu Kanai, Yosuke Takei, Masahiko Kawagishi & Nobutaka Hirokawa

  2. Department of Microbiology, College of Medicine, Inje University, Jingu, Busan, 633-165, Korea

    Dae-Hyung Seog

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  1. Mitsutoshi Setou
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Correspondence to Nobutaka Hirokawa.

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Setou, M., Seog, DH., Tanaka, Y. et al. Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites. Nature 417, 83–87 (2002). https://doi.org/10.1038/nature743

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