Nature Cell Biology
1, E12 (1999)
doi:10.1038/8962
A method for movementSally H. ZigmondSally H. Zigmond is at the Biology Department, University of Pennsylvania, 415 South University Ave, Philadelphia, Pennsylvania 19104-6018, USA.
Correspondence should be addressed to Sally H. Zigmond szigmond@sas.upenn.eduDuring cell movement, microtubules may control the actin cytoskeleton through
specific Rho GTPases. An understanding of the spatial control of cell motility
may now be within reach.Cell movement is a highly coordinated process. First, the front of the
cell protrudes and then attaches to the substratum on which the cell is moving.
Then, the cytoplasm moves forward. Finally, the cell's rear releases its attachments
to the substratum and moves forward. All of these steps depend on localized
polymerization of the cytoskeletal protein actin, which forms different structures
in different parts of the motile cell. Specific active GTP-hydrolysing proteins
(GTPases) of the Rho family1,
2 can induce these processes.
Microtubule dynamics can also coordinate actin-based movements —
for example, when microtubules depolymerize, a cell loses polarity and its
migration speed slows3,
4,
5. Are Rho GTPases, microtubule dynamics
and actin polymerization linked? Studies of the Rho proteins Rho and Rac by
Ren and colleagues6 and Waterman-Storer and co-workers7 now suggest an answer.
If we want to understand exactly how Rho GTPases could be linked to microtubule
dynamics and actin polymerization, we need to be able to assay when and where
in the cell they are active. Rho proteins are active when they bind GTP, and
inactive when they bind GDP. So we need to know how many of the proteins are
in their GTP-bound form when known microtubule and actin dynamics are taking
place. For this purpose, Waterman-Storer et al.7 and
Ren et al.6 have used a new "pull-down" assay (Fig. 1).
 | | |
The new assay of Rho activation6 helps to explain how microtubule
depolymerization decreases cell movement and increases the contractile force
that cells impart to the substratum3,
5. It was thought that
microtubule depolymerization might increase force by merely removing an internal
mechanical constraint on contraction8. Alternatively, depolymerization
might stimulate contraction of actin−myosin chains, as increased phosphorylation
of the myosin light chain follows microtubule depolymerization9.
Rho stimulates this phosphorylation and inhibitors of Rho block both the increased
force and the phosphorylation10,
11. Now Ren et al.6 show that induction of microtubule depolymerization by the drug
colchicine in 3T3 fibroblasts activates Rho, as determined in a pull-down
assay; active Rho then stimulates cytoplasmic contraction9,
10,
11.
Active Rac, in contrast, can induce the formation of cell protrusions,
and so enhances cell motility. Microtubule dynamics can also modulate cell
protrusions, and Waterman-Storer et al.7 reveal how Rac
and microtubules can be linked to enhance actin polymerization and the formation
of protrusions. Protrusion at the cell surface decreases following depolymerization
of microtubules by the drug nocodazole4. Waterman-Storer
et al.7 show that when nocodazole is washed out and microtubules
reassemble, protrusive activity increases. It seems not to be the amount of
polymerized microtubules that is important, but rather their dynamics —
the changes between periods of microtubule depolymerization and polymerization.
If microtubule dynamics are blocked, cell migrations and surface protrusions
are inhibited12,
13,
14.
Are the effects of these microtubule dynamics on actin polymerization mediated
through Rac? The answer is probably "yes" — Waterman-Storer et al.
7 show that dominant-negative Rac blocks the increased protrusion
induced by microtubule dynamics, and that microtubule polymerization increases
the amount of active Rac detected in a pull-down assay. Their studies of Rac
are also consistent with the idea that it is the microtubule dynamics, rather
than the amount of microtubules, that are important.
It isn't clear how microtubule dynamics modulate the levels
of active Rho and Rac. One clue is that microtubules co-localize with several
guanine-nucleotide-exchange factors with activities for Rho and Rac15,
16
— these exchange proteins control whether Rho and Rac are active or
inactive. Rac itself also associates with tubulin and/or microtubules7, as do other proteins that may indirectly regulate Rho or Rac.
Different microtubule dynamics, therefore, increase levels of active Rho
or Rac, and Rho and Rac in turn have different effects on cell motility. Might
the effects of microtubule dynamics, acting through Rac and Rho, also act
at a subcellular level — to coordinate the different processes that
go on in different parts of the cell during movement? The cell front contains
the highest density of dynamically unstable microtubule ends7,
and Waterman-Storer et al. propose that this dynamic instability, acting
through Rac, is what causes protrusion to localize at the front. Further back
in the cell, net microtubule depolymerization17 might locally
activate Rho and increase cytoplasmic contractility18. It seems
possible that, in large cells, microtubule dynamics can help coordinate cell
motility by modulating Rho and Rac.
REFERENCES
-
Ridley, A. et al. Cell 70, 401−410 (1992). | Article | PubMed | ISI | ChemPort |
-
Nobes, C. D. & Hall, A. J. Cell Biol. 144, 1235−1244 (1999). | Article | PubMed | ISI | ChemPort |
-
Danowski, B. J. Cell Sci. 93, 255−266 (1989). | ChemPort |
-
Bershadsky, A. D., Vaisberg, E. A. & Vasiliev, J. M. Cell Motil. Cytoskeleton 19, 152−158 (1991). | PubMed | ISI | ChemPort |
-
Bershadsky, A., Chausovsky, A, Becker, E., Lyubimova, A. & Geiger, B. Curr. Biol. 6, 1279−1289 (1996). | Article | PubMed | ISI | ChemPort |
-
Ren, X.-D., Kiosses, W. B. & Schwartz, M. A. EMBO J. 18, 578−585 (1999). | Article | PubMed | ISI | ChemPort |
-
Waterman-Storer, C. M., Worthylake, R. A., Liu, B. P., Burridge, K. & Salmon, E. D. Nature Cell Biol. 1, 45−50 (1999). | Article | PubMed | ISI | ChemPort |
-
Ingber, D. E. J. Cell Sci. 104, 613−627 (1993). | PubMed | ISI |
-
Kolodney, M. & Elson, E. Proc. Natl Acad. Sci. USA 92, 10252−10256 (1995). | PubMed | ChemPort |
-
Enomoto, T. Cell Struct. Funct. 21, 317−326 (1996). | PubMed | ISI | ChemPort |
-
Liu, B.P., Chrzanowske-Wodnicka, M. & Burridge, K. Cell Adhesion Commun. 5, 249−255 (1998). | ISI | ChemPort |
-
Tanaka, E., Ho, T & Kirschner, M. W. J. Cell Biol. 128, 139−155 (1995). | Article | PubMed | ISI | ChemPort |
-
Mikhailov, A. & Gundersen, G. G. Cell Motil. Cytoskel. 41, 325−340 (1998). | Article | ISI | ChemPort |
-
Liao, G., Nagasaki, T. & Gundersen, G. G. J. Cell Sci. 108, 3473−3483 (1995). | PubMed | ISI | ChemPort |
-
Ren, Y. et al. J. Biol. Chem. 273, 34954−34960 (1998). | Article | PubMed | ISI | ChemPort |
-
Glaven, J. A. et al. J. Biol. Chem. 274, 2279−2285 (1999). | Article | PubMed | ISI | ChemPort |
-
Waterman-Storer, C. & Salmon, E. D. J. Cell Biol. 139, 417−434 (1997). | Article | PubMed | ChemPort |
-
Waterman-Storer, C.M. & Salmon, E. D. Curr. Opin. Cell Biol. 11, 61−67 (1999). | Article | PubMed | ISI | ChemPort |
|
