Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 319 (5866): 1086-1089

Copyright © 2008 by the American Association for the Advancement of Science

Differential Regulation of Dynein and Kinesin Motor Proteins by Tau

Ram Dixit, Jennifer L. Ross,* Yale E. Goldman, Erika L. F. Holzbaur{dagger}

Abstract: Dynein and kinesin motor proteins transport cellular cargoes toward opposite ends of microtubule tracks. In neurons, microtubules are abundantly decorated with microtubule-associated proteins (MAPs) such as tau. Motor proteins thus encounter MAPs frequently along their path. To determine the effects of tau on dynein and kinesin motility, we conducted single-molecule studies of motor proteins moving along tau-decorated microtubules. Dynein tended to reverse direction, whereas kinesin tended to detach at patches of bound tau. Kinesin was inhibited at about a tenth of the tau concentration that inhibited dynein, and the microtubule-binding domain of tau was sufficient to inhibit motor activity. The differential modulation of dynein and kinesin motility suggests that MAPs can spatially regulate the balance of microtubule-dependent axonal transport.

Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.

* Present address: 302 Hasbrouck Laboratory, Department of Physics, University of Massachusetts at Amherst, Amherst, MA 01003, USA.

{dagger} To whom correspondence should be addressed. E-mail: holzbaur{at}

Loss of the m-AAA protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation.
A. K. Kondadi, S. Wang, S. Montagner, N. Kladt, A. Korwitz, P. Martinelli, D. Herholz, M. J. Baker, A. C. Schauss, T. Langer, et al. (2014)
   Abstract »    Full Text »    PDF »
The Mixture of "Ecstasy" and its Metabolites Impairs Mitochondrial Fusion/Fission Equilibrium and Trafficking in Hippocampal Neurons, at In Vivo Relevant Concentrations.
D. J. Barbosa, R. Serrat, S. Mirra, M. Quevedo, E. G. de Barreda, J. Avila, L. M. Ferreira, P. S. Branco, E. Fernandes, M. de Lourdes Bastos, et al. (2014)
Toxicol. Sci.
   Abstract »    Full Text »    PDF »
Presenilin influences glycogen synthase kinase-3 {beta} (GSK-3{beta}) for kinesin-1 and dynein function during axonal transport.
K. Dolma, G. J. Iacobucci, K. Hong Zheng, J. Shandilya, E. Toska, J. A. White II, E. Spina, and S. Gunawardena (2014)
Hum. Mol. Genet. 23, 1121-1133
   Abstract »    Full Text »    PDF »
The influence of dynein processivity control, MAPs, and microtubule ends on directional movement of a localising mRNA.
H. C. Soundararajan and S. L. Bullock (2014)
eLife Sci 3, e01596
   Abstract »    Full Text »    PDF »
Motor Domain Phosphorylation Modulates Kinesin-1 Transport.
H. A. DeBerg, B. H. Blehm, J. Sheung, A. R. Thompson, C. S. Bookwalter, S. F. Torabi, T. A. Schroer, C. L. Berger, Y. Lu, K. M. Trybus, et al. (2013)
J. Biol. Chem. 288, 32612-32621
   Abstract »    Full Text »    PDF »
Amyloid-{beta} oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons.
E. M. Ramser, K. J. Gan, H. Decker, E. Y. Fan, M. M. Suzuki, S. T. Ferreira, and M. A. Silverman (2013)
Mol. Biol. Cell 24, 2494-2505
   Abstract »    Full Text »    PDF »
JIP1 regulates the directionality of APP axonal transport by coordinating kinesin and dynein motors.
M.-m. Fu and E. L. F. Holzbaur (2013)
J. Cell Biol. 202, 495-508
   Abstract »    Full Text »    PDF »
Therapeutic strategies for tau mediated neurodegeneration.
Y. Yoshiyama, V. M. Y. Lee, and J. Q. Trojanowski (2013)
J. Neurol. Neurosurg. Psychiatry 84, 784-795
   Abstract »    Full Text »    PDF »
Microtubule-based transport - basic mechanisms, traffic rules and role in neurological pathogenesis.
M. A. M. Franker and C. C. Hoogenraad (2013)
J. Cell Sci. 126, 2319-2329
   Abstract »    Full Text »    PDF »
Activation of conventional kinesin motors in clusters by Shaw voltage-gated K+ channels.
J. Barry, M. Xu, Y. Gu, A. W. Dangel, P. Jukkola, C. Shrestha, and C. Gu (2013)
J. Cell Sci. 126, 2027-2041
   Abstract »    Full Text »    PDF »
In vivo optical trapping indicates kinesin's stall force is reduced by dynein during intracellular transport.
B. H. Blehm, T. A. Schroer, K. M. Trybus, Y. R. Chemla, and P. R. Selvin (2013)
PNAS 110, 3381-3386
   Abstract »    Full Text »    PDF »
Tau Loss Attenuates Neuronal Network Hyperexcitability in Mouse and Drosophila Genetic Models of Epilepsy.
J. K. Holth, V. C. Bomben, J. G. Reed, T. Inoue, L. Younkin, S. G. Younkin, R. G. Pautler, J. Botas, and J. L. Noebels (2013)
J. Neurosci. 33, 1651-1659
   Abstract »    Full Text »    PDF »
Motor transport of self-assembled cargos in crowded environments.
L. Conway, D. Wood, E. Tuzel, and J. L. Ross (2012)
PNAS 109, 20814-20819
   Abstract »    Full Text »    PDF »
In Vivo Imaging of Disease-Related Mitochondrial Dynamics in a Vertebrate Model System.
G. Plucinska, D. Paquet, A. Hruscha, L. Godinho, C. Haass, B. Schmid, and T. Misgeld (2012)
J. Neurosci. 32, 16203-16212
   Abstract »    Full Text »    PDF »
Tau Protein Diffuses along the Microtubule Lattice.
M. H. Hinrichs, A. Jalal, B. Brenner, E. Mandelkow, S. Kumar, and T. Scholz (2012)
J. Biol. Chem. 287, 38559-38568
   Abstract »    Full Text »    PDF »
Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration.
E.-M. Mandelkow and E. Mandelkow (2012)
Cold Spring Harb Perspect Med 2, a006247
   Abstract »    Full Text »    PDF »
The axonal transport of mitochondria.
W. M. Saxton and P. J. Hollenbeck (2012)
J. Cell Sci. 125, 2095-2104
   Abstract »    Full Text »    PDF »
Synapses and Alzheimer's Disease.
M. Sheng, B. L. Sabatini, and T. C. Sudhof (2012)
Cold Spring Harb Perspect Biol 4, a005777
   Abstract »    Full Text »    PDF »
Molecular crowding creates traffic jams of kinesin motors on microtubules.
C. Leduc, K. Padberg-Gehle, V. Varga, D. Helbing, S. Diez, and J. Howard (2012)
PNAS 109, 6100-6105
   Abstract »    Full Text »    PDF »
The impacts of molecular motor traffic jams.
J. L. Ross (2012)
PNAS 109, 5911-5912
   Full Text »    PDF »
Tau's role in the developing brain: implications for intellectual disability.
T. Sapir, M. Frotscher, T. Levy, E.-M. Mandelkow, and O. Reiner (2012)
Hum. Mol. Genet. 21, 1681-1692
   Abstract »    Full Text »    PDF »
Two independent switches regulate cytoplasmic dynein's processivity and directionality.
W. J. Walter, M. P. Koonce, B. Brenner, and W. Steffen (2012)
PNAS 109, 5289-5293
   Abstract »    Full Text »    PDF »
Ndel1-derived peptides modulate bidirectional transport of injected beads in the squid giant axon.
M. Segal, I. Soifer, H. Petzold, J. Howard, M. Elbaum, and O. Reiner (2012)
Biology Open 1, 220-231
   Abstract »    Full Text »    PDF »
The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice.
B. Zhang, J. Carroll, J. Q. Trojanowski, Y. Yao, M. Iba, J. S. Potuzak, A.-M. L. Hogan, S. X. Xie, C. Ballatore, A. B. Smith III, et al. (2012)
J. Neurosci. 32, 3601-3611
   Abstract »    Full Text »    PDF »
{gamma}-Aminobutyric Acid Type A (GABAA) Receptor Activation Modulates Tau Phosphorylation.
N.-P. Nykanen, K. Kysenius, P. Sakha, P. Tammela, and H. J. Huttunen (2012)
J. Biol. Chem. 287, 6743-6752
   Abstract »    Full Text »    PDF »
Regulation of Mitochondrial Transport and Inter-Microtubule Spacing by Tau Phosphorylation at the Sites Hyperphosphorylated in Alzheimer's Disease.
K. Shahpasand, I. Uemura, T. Saito, T. Asano, K. Hata, K. Shibata, Y. Toyoshima, M. Hasegawa, and S.-i. Hisanaga (2012)
J. Neurosci. 32, 2430-2441
   Abstract »    Full Text »    PDF »
The Nucleotide-binding State of Microtubules Modulates Kinesin Processivity and the Ability of Tau to Inhibit Kinesin-mediated Transport.
D. P. McVicker, L. R. Chrin, and C. L. Berger (2011)
J. Biol. Chem. 286, 42873-42880
   Abstract »    Full Text »    PDF »
Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation.
S. S. Ambegaokar and G. R. Jackson (2011)
Hum. Mol. Genet. 20, 4947-4977
   Abstract »    Full Text »    PDF »
Directionality of individual kinesin-5 Cin8 motors is modulated by loop 8, ionic strength and microtubule geometry.
A. Gerson-Gurwitz, C. Thiede, N. Movshovich, V. Fridman, M. Podolskaya, T. Danieli, S. Lakamper, D. R. Klopfenstein, C. F. Schmidt, and L. Gheber (2011)
EMBO J. 30, 4942-4954
   Abstract »    Full Text »    PDF »
Mutually Exclusive Cytoplasmic Dynein Regulation by NudE-Lis1 and Dynactin.
R. J. McKenney, S. J. Weil, J. Scherer, and R. B. Vallee (2011)
J. Biol. Chem. 286, 39615-39622
   Abstract »    Full Text »    PDF »
TPX2 regulates the localization and activity of Eg5 in the mammalian mitotic spindle.
N. Ma, J. Titus, A. Gable, J. L. Ross, and P. Wadsworth (2011)
J. Cell Biol. 195, 87-98
   Abstract »    Full Text »    PDF »
Important neuronal toxicity of microtubule-bound Tau in vivo in Drosophila.
Y. Talmat-Amar, Y. Arribat, C. Redt-Clouet, S. Feuillette, A.-L. Bouge, M. Lecourtois, and M.-L. Parmentier (2011)
Hum. Mol. Genet. 20, 3738-3745
   Abstract »    Full Text »    PDF »
Developing Therapeutic Approaches to Tau, Selected Kinases, and Related Neuronal Protein Targets.
V. M.-Y. Lee, K. R. Brunden, M. Hutton, and J. Q. Trojanowski (2011)
Cold Spring Harb Perspect Med 1, a006437
   Abstract »    Full Text »    PDF »
Myosin Va and myosin VI coordinate their steps while engaged in an in vitro tug of war during cargo transport.
M. Y. Ali, G. G. Kennedy, D. Safer, K. M. Trybus, H. L. Sweeney, and D. M. Warshaw (2011)
PNAS 108, E535-E541
   Abstract »    Full Text »    PDF »
Sunday Driver/JIP3 binds kinesin heavy chain directly and enhances its motility.
F. Sun, C. Zhu, R. Dixit, and V. Cavalli (2011)
EMBO J. 30, 3416-3429
   Abstract »    Full Text »    PDF »
Kinesin-1 transport reductions enhance human tau hyperphosphorylation, aggregation and neurodegeneration in animal models of tauopathies.
T. L. Falzone, S. Gunawardena, D. McCleary, G. F. Reis, and L. S. B. Goldstein (2010)
Hum. Mol. Genet. 19, 4399-4408
   Abstract »    Full Text »    PDF »
Tau Reduction Prevents A{beta}-Induced Defects in Axonal Transport.
K. A. Vossel, K. Zhang, J. Brodbeck, A. C. Daub, P. Sharma, S. Finkbeiner, B. Cui, and L. Mucke (2010)
Science 330, 198
   Abstract »    Full Text »    PDF »
Trafficking Guidance Receptors.
B. Winckler and I. Mellman (2010)
Cold Spring Harb Perspect Biol 2, a001826
   Abstract »    Full Text »    PDF »
Tau Potentiates Nerve Growth Factor-induced Mitogen-activated Protein Kinase Signaling and Neurite Initiation without a Requirement for Microtubule Binding.
C. J. Leugers and G. Lee (2010)
J. Biol. Chem. 285, 19125-19134
   Abstract »    Full Text »    PDF »
Microtubule-associated Protein-like Binding of the Kinesin-1 Tail to Microtubules.
M. A. Seeger and S. E. Rice (2010)
J. Biol. Chem. 285, 8155-8162
   Abstract »    Full Text »    PDF »
Correction of tau mis-splicing caused by FTDP-17 MAPT mutations by spliceosome-mediated RNA trans-splicing.
T. Rodriguez-Martin, K. Anthony, M. A. Garcia-Blanco, S. G. Mansfield, B. H. Anderton, and J.-M. Gallo (2009)
Hum. Mol. Genet. 18, 3266-3273
   Abstract »    Full Text »    PDF »
Phosphorylated Tau Interacts with c-Jun N-terminal Kinase-interacting Protein 1 (JIP1) in Alzheimer Disease.
L. M. Ittner, Y. D. Ke, and J. Gotz (2009)
J. Biol. Chem. 284, 20909-20916
   Abstract »    Full Text »    PDF »
Neuronal Migration and Neurodegeneration: 2 Sides of the Same Coin.
O. Reiner, A. Shmueli, and T. Sapir (2009)
Cereb Cortex 19, i42-i48
   Abstract »    Full Text »    PDF »
Axonal Stress Kinase Activation and Tau Misbehavior Induced by Kinesin-1 Transport Defects.
T. L. Falzone, G. B. Stokin, C. Lillo, E. M. Rodrigues, E. L. Westerman, D. S. Williams, and L. S. B. Goldstein (2009)
J. Neurosci. 29, 5758-5767
   Abstract »    Full Text »    PDF »
Inhibition of Tobacco Mosaic Virus Movement by Expression of an Actin-Binding Protein.
C. Hofmann, A. Niehl, A. Sambade, A. Steinmetz, and M. Heinlein (2009)
Plant Physiology 149, 1810-1823
   Abstract »    Full Text »    PDF »
Tau Mutations in Neurodegenerative Diseases.
M. S. Wolfe (2009)
J. Biol. Chem. 284, 6021-6025
   Abstract »    Full Text »    PDF »
Tau deletion exacerbates the phenotype of Niemann-Pick type C mice and implicates autophagy in pathogenesis.
C. D. Pacheco, M. J. Elrick, and A. P. Lieberman (2009)
Hum. Mol. Genet. 18, 956-965
   Abstract »    Full Text »    PDF »
The Drosophila BEACH Family Protein, Blue Cheese, Links Lysosomal Axon Transport with Motor Neuron Degeneration.
A. Lim and R. Kraut (2009)
J. Neurosci. 29, 951-963
   Abstract »    Full Text »    PDF »
Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia.
L. M. Ittner, T. Fath, Y. D. Ke, M. Bi, J. van Eersel, K. M. Li, P. Gunning, and J. Gotz (2008)
PNAS 105, 15997-16002
   Abstract »    Full Text »    PDF »
Capital Cells: The American Society for Cell Biology, Washington, D.C., December 1-5, 2007.
N. LeBrasseur and R. Williams (2008)
J. Cell Biol. 180, 654-659
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882