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How do microtubules guide migrating cells?

Nature Reviews Molecular Cell Biology volume 3, pages 957–964 (2002)Cite this article

Abstract

Microtubules have long been implicated in the polarization of migrating cells, but how they carry out this role is unclear. Here, we propose that microtubules determine cell polarity by modulating the pattern of adhesions that a cell develops with the underlying matrix, through focal inhibitions of contractility.

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Figure 1: The actin cytoskeleton and adhesion sites in a migrating cell.
Figure 2: Changes in the actin cytoskeleton and adhesion sites in a migrating cell.
Figure 3: Focal adhesion growth in response to the local application of external force.
Figure 4: Microtubule disruption triggers focal adhesion growth.
Figure 5: Microtubules target substrate adhesion complexes.
Figure 6: Asymmetric relaxation of contractility restores polarization in fibroblasts lacking microtubules.
Figure 7: Microtubule–adhesion-site crosstalk in a migrating cell.

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Acknowledgements

We thank O. Krylyskina and G. Resch for their invaluable help with the videos and animation. A.B. and B.G. are grateful to D. Riveline and J. Kirchner for providing the experimental data for figures 2 and 3. A. Huttenlocher is acknowledged for providing the DsRed zyxin construct that was used in figure 5. This work was supported in part by a grant from the Austrian Science Research Council to J.V.S. and I.K. B.G. is the incumbent of the E. Neter Chair in Cell and Tumor Biology; A.B. holds the J. Moss Chair of Biomedical Research.

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Authors and Affiliations

  1. the Institute of Molecular Biology, Austrian Academy of Sciences, Billrothstrasse 11, Salzburg, 5020, Austria

    J. Victor Small & Irina Kaverina

  2. the Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Benjamin Geiger & Alexander Bershadsky

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  1. J. Victor Small
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Correspondence to J. Victor Small.

Supplementary information

Online Video 1

A time-lapse video of a goldfish fibroblast that was expressing green fluorescent protein (GFP)–actin (green) and that was also micro-injected with rhodamine-tagged vinculin (red) to mark adhesion complexes (corresponding to Fig. 1). The inset movies correspond to the boxed areas I and IV in Fig. 1. Video 1.1 corresponds to boxed area I, which is shown in Fig. 1b,c and Fig. 2a, and shows newly forming adhesions. Video 1.2 corresponds to the boxed area IV in Fig. 2c and shows sliding, trailing adhesions. The time between frame-pairs in the Quick-Time videos is 60 s for video 1 and 30 s for videos 1.1 and 1.2; the interval between the sequential frames in the GFP and rhodamine channels is 1 s. The online video was provided by O. Krylyshkina. (MOV 128 kb)

Online Video 1.1

Video 1.1 corresponds to boxed area I, which is shown in Fig. 1b,c and Fig. 2a, and shows newly forming adhesions. (MOV 4046 kb)

Online Video 1.2

Video 1.2 corresponds to the boxed area IV in Fig. 2c and shows sliding, trailing adhesions. The time between frame-pairs in the Quick-Time videos is 60 s for video 1 and 30 s for videos 1.1 and 1.2; the interval between the sequential frames in the GFP and rhodamine channels is 1 s. (MOV 5598 kb)

Online Video 2

The targeting of substrate adhesion complexes by microtubules is shown (corresponding to Fig. 5). The video shows a peripheral region of a goldfish fibroblast thatwas transfected with green fluorescent protein–tubulin (green) and DsRed–zyxin (red). The time between frame-pairs was 10 s, with 1 s between the two fluorescent channels in one pair. The targeting events are circled in arrested frames and the inset movies show specific details. Video 2.1 highlights the multiple targeting of one focal adhesion by several microtubules (circled events), as well as the re-routing of one microtubule away from this adhesion to more peripheral adhesions (asterisk). Video 2.2 shows the dissolution of two focal adhesions (circled) after several targeting events. (MOV 513 kb)

Online Video 2.1

Video 2.1 highlights the multiple targeting of one focal adhesion by several microtubules (circled events), as well as the re-routing of one microtubule away from this adhesion to more peripheral adhesions (asterisk). (MOV 11190 kb)

Online Video 2.2

Video 2.2 shows the dissolution of two focal adhesions (circled) after several targeting events. (MOV 5095 kb)

Online Video 3

An animation depicting the salient features of the interactions between microtubules and sites of substrate adhesion. In a migrating cell, protrusion is supported by the formation of focal complexes at the cell front, which can then develop into focal adhesions. the cell rear is limited by focal adhesions that originate through the retraction of former regions of protrusion. Targeting of focal adhesions by microtubules is presumed to be associated with the transmission of a signal (orange stars) that promotes events leading to adhesion disassembly. Targeting of focal adhesions behind the cell front is required to promote adhesion turnover and facilitate further protrusion. Targeting of focal adhesions at the rear is more frequent and is required to promote adhesion release during retraction. The animation programme does not allow a realistic simulation of microtubule dynamics. Provided by G. Resch, Austrian Academy of Science, Austria. (MOV 6402 kb)

41580_2002_BFnrm971_MOESM8_ESM.jpg

Online figure 1 | Microtubule disruption induces stress fibre growth. The activation of actin stress-fibre assembly (right panels) in starved fibroblasts after the initiation of microtubule depolymerization by nocodazole (left panels) is shown. Reproduced with permission from Ref. 25 © (2002) Elsevier Science. (JPG 43 kb)

41580_2002_BFnrm971_MOESM9_ESM.jpg

Online figure 2 | Repetitive targeting of peripheral focal adhesins precedes cell-edge retraction. An example of the multiple targeting of a peripheral adhesion site by microtubules that leads to adhesion translocation and detachment. The panels show video sequences from the periphery of a goldfish fibroblast that was injected with Cy-3-tagged tubulin and rhodamine-tagged vinculin. Times are in minutes and seconds. Different adhesion sites are targeted at different time points, and the frames were selected for the targeting events of one adhesion. Reproduced with permission from Ref. 31 © (2002) The Rockefeller University Press. (JPG 23 kb)

41580_2002_BFnrm971_MOESM10_ESM.jpg

Online figure 3 | Microtubule polymerization dynamics are influenced by mechanical stress in the actin cytoskeleton. The feedback regulation of microtubules by the actin cytoskeleton. Transient relaxation of peripheral contractility induces microtubule depolymerization. A fish fibroblast that was transfected with green fluorescent protein–tubulin (green) and micro-injected with rhodamine-tagged vinculin (red) was exposed for 2–3 min on one edge to the myosin relaxant, ML-7, which was delivered through a micropipette. The first two panels show images before and after application. After removal of the drug (recovery), microtubules repolymerize to the cell edge and target adhesion sites (panel 3). Modified with permission from Ref. 19 © (2002) The Company of Biologists Ltd. (JPG 26 kb)

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Rho kinase

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Small, J., Geiger, B., Kaverina, I. et al. How do microtubules guide migrating cells?. Nat Rev Mol Cell Biol 3, 957–964 (2002). https://doi.org/10.1038/nrm971

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