review

Adhesion assembly, disassembly and

turnover in migrating cells – over and
over and over again
Donna J. Webb*†, J. Thomas Parsons‡ and Alan F. Horwitz*
*Department of Cell Biology, and ‡Department of Microbiology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA
†e-mail: djw2p@virginia.edu

f focus on
signalling and adhesion
Cell migration is an integrated process that requires the continuous, coordinated formation and disassembly of
adhesions. These processes are complex and require a regulated interaction of numerous molecules, and the acti-
vation of specific signalling pathways. Even though understanding these processes is challenging, important insights
are beginning to emerge, and the technology to facilitate significant advances in this area is now in place.

C
ell migration is central to many biological and pathological
processes, including embryogenesis, the inflammatory
response, tissue repair and regeneration, cancer, arthritis,
atherosclerosis, osteoporosis, as well as congenital developmental
brain defects1. Not surprisingly, there is considerable interest in
understanding the molecular basis of cell migration because this
could lead to new therapeutic strategies for various pathological
processes. But understanding migration is challenging, because it
requires the integration and temporal coordination of many differ-
ent processes that occur in spatially distinct locations in the cell.
This space/time integration is becoming a focus for much of the
current research in cell migration2,3 and will be addressed here pri-
marily in the context of adhesion formation and disassembly.
Migration can be viewed as a multistep cycle. The basic migrato-
ry cycle includes extension of a protrusion, formation of stable
attachments near the leading edge of the protrusion, translocation
of the cell body forward, release of adhesions and retraction at the
cell rear1,4,5. Polymerization of the actin cytoskeletal network drives
the initial extension of the plasma membrane at the cell front6–8. The
interaction of the integrin family of transmembrane receptors with
the extracellular matrix stabilizes the adhesions by recruiting sig-
nalling and cytoskeletal proteins9–13. These small, nascent adhesions
may transmit strong forces, and serve as traction points for the
propulsive forces that move the cell body forward14–18. Release of
adhesions and retraction at the rear completes the migratory cycle
allowing net translocation of the cell in the direction of movement.
Over 50 proteins have been found in adhesions19. The classifica-
tion of adhesions, which include focal adhesions, fibrillar adhe-
sions, focal complexes and podosomes, is based primarily on mor-
phology or method of formation. For example, fibrillar adhesions
are central structures that contain α5β1 integrin, tensin and
actopaxin19–21, whereas focal complexes are small adhesions
induced by Rac activation at the periphery of the cell22,23. It is the
small adhesions at the cell front, undetectable in some cell types,
that drive rapid cell migration14,18,24,25. Under tension, these small
adhesions can mature into larger, more organized adhesions, such
as focal adhesions9,26–29. Focal adhesions, which have been inten-
sively studied, are relatively stable structures and tend to inhibit cell
migration. They seem to be involved in the generation of contrac-
tile forces that function in processes unrelated to migration, such as
the formation and remodeling of extracellular matrices30. It is
becoming apparent that different classes of adhesions reflect differ-
ing molecular compositions. It is likely, therefore, that adhesions,
even in migrating cells, will show heterogeneity as their molecular
characterizations emerge.
The mechanisms by which adhesions turnover and the mecha-
nisms that regulate these processes are not well understood. The
formation and disassembly of adhesions are complex processes and
require a coordinated interaction of actin or actin-binding pro-
teins, signalling molecules, structural proteins, integrins, adaptor
molecules and microtubules. Understanding adhesion turnover in
migrating cells and the mechanisms underlying this process is now
a critical area of emerging interest. In this review, we outline the
issues, knowledge, and opportunities in studies of adhesion
turnover. The emphasis is on several emerging themes: assays for
adhesion dynamics (Fig. 1), delineating the mechanisms that regu-
late turnover versus maturation of adhesions, effectors of adhesion
assembly, and the transport of integrins in vesicles and signalling
components in complexes.
The leading edge
The formation of a protrusion initiates the migration cycle; but for
migration to occur, the protrusion must stabilize by attaching to
the substratum. The leading edge, which for our purposes refers to
the membrane and adjacent region containing cortical actin at the
front of the protrusion, seems to be the site of action for both the
formation and stabilization of protrusions. When fluorescently
labelled G-actin is microinjected into fibroblasts, it is first incorpo-
rated at the leading edge where it polymerizes31. This actin poly-
merization promotes extension of the lamellipodium. Proteins that
regulate actin dynamics and organization, such as vasodilator-
stimulated phosphoprotein (VASP), Wiskott–Aldrich syndrome
protein (WASP), profilin and the Arp 2/3 complex, localize to the
periphery of protruding lamellipodia32–36. Regulators of actin poly-
merization and protrusion formation, such as activated Rac and its
effector, p21-activated kinase (PAK), also localize at or very near
the leading edge2,3. In addition, adhesion-related molecules, includ-
ing VASP, integrins, α-actinin and G-protein-coupled receptor-
kinase-interacting protein 1 (GIT1) are present at the leading edge
membrane32,37–39. These proteins probably function to link the
growing actin filaments at the leading edge to the substratum and
to initiate or coordinate signals that regulate this process. But the
nature of the initial association of adhesive receptors with actin is
unclear. It seems that the association is with cortical actin rather
than the highly bundled actin characteristic of stress fibres. The
nature and function of the early signals initiated from adhesive
receptors as the nascent adhesions form and the mechanisms by
which Rho family proteins regulate the formation of adhesions are
also unclear at present.

NATURE CELL BIOLOGY VOL 4 APRIL 2002 http://cellbio.nature.com E97

© 2002 Macmillan Magazines Ltd

review
t = 0 sec t = 300 sec
Figure 1 Assay for measuring adhesion turnover in migrating cells.
The intensity of paxillin adhesions (false-colored green) at the base of
Current evidence indicates that the formation of nascent-
cell–substratum contact sites at the leading edge and the formation
of a protrusion are directly coupled in rapidly migrating cells24. It is
important to note that not all protrusions are stabilized by adhesion
complexes. During migration in vivo, cells extend and retract pro-
trusions for long periods of time suggesting that the stabilization of
a protrusion may depend on ligand or receptor density at the lead-
ing edge40. Signals that modulate integrin avidity or affinity may also
regulate the adhesions and stabilization of the protrusions38,41.
Assembly of adhesions in migrating cells
Although the mechanisms by which adhesions assemble are only
beginning to be addressed, some directions are emerging. Current
evidence favours the sequential recruitment of individual, or class-
es of, adhesion components around a nucleation center rather than
the stabilization of large, preformed cytoskeletal complexes.
Polystyrene beads coated with integrin ligands or antibodies that
mimic the ligand-bound state or aggregation of integrins, have
been used to show that the aggregation of integrins induces
recruitment of focal adhesion kinase (FAK) and tensin10,11. If tyro-
sine phosphorylation is inhibited, the large accumulation of sig-
nalling molecules does not occur. Importantly, both ligand binding
and aggregation are necessary for cytoskeletal proteins such as α-
actinin, vinculin and talin to be recruited10–12. Adhesion assembly
was studied in migrating cells using pairs of adhesion components
fused to green fluorescent protein (GFP) or its derivatives37. This
study shows that paxillin and α-actinin are recruited sequentially
to adhesions37. Recent observations suggest that some signalling
components, such as PAK and PAK-interacting exchange factor
(PIX), enter adhesions as small, preformed complexes with pax-
illin39,42. To date, there is little evidence to suggest that large, pre-
assembled cytoskeletal complexes are stabilized by association with
and tethering to integrins as previously suggested43,44. Although
these studies support a regulated, sequential model, it also seems
that, in some cases, components may enter simultaneously, either
individually or in preformed complexes. Additional measurements
of the kinetics of adhesion assembly using single and multiple flu-
orescently tagged molecules should provide a clearer picture.
Adhesion disassembly and turnover in migrating
cells
Adhesion disassembly is observed both at the cell rear, where it pro-
motes rear retraction, and at the cell front, where it accompanies
the formation of new protrusions and adhesions. Because the
mechanisms at these two locations differ, we will refer to the former
as disassembly and the latter as turnover. At the rear of migrating
cells, the release of adhesions results in retraction of the cell tail and
E98
© 2002 Macmillan Magazines Ltd
t = 600 sec
new protrusions decreases and eventually disappears as new adhesions
(false-colored red) form at the leading edge. Scale bar, 20 µm.
a net translocation of the cell body forward. The weakening or sev-
ering of the integrin–extracellular matrix (ECM) linkage is at least
partially driven by contractile forces45–47. Under these conditions,
the integrin remains associated with the substrate and the intracel-
lular adhesive components, which are under tension, slide toward
the cell body and eventually ‘disperse’. Cytoskeletal components,
such as paxillin and α-actinin, have not been seen in ‘footprints’
behind the cell indicating that the cleavage of the cytoskeletal link-
age occurs at or very close to integrin37. The translocation of adhe-
sion components has also been reported by several others20,21,46,48,49.
Recently, photobleaching was used to show an increase in diffusion
of β3 integrins in the sliding adhesions at the rear as compared with
the stationary adhesions at the front suggesting a decrease in affin-
ity or avidity of the integrins for one or more of the molecules with
which they associate49.
Adhesion disassembly does not seem to be a simple reversal of
the assembly mechanism. At the cell rear, paxillin and α-actinin
leave adhesions at approximately the same time, whereas these mol-
ecules are recruited to adhesions sequentially37. In another study,
zyxin and paxillin were found to be early components of newly
forming adhesions; but zyxin leaves before paxillin as the adhesions
disassemble at the rear36.
At the cell front, paxillin-containing adhesions at the base of a
protrusion cycle turn over as new adhesions form at the leading
edge37 (Fig. 1). The molecular composition of these adhesions, at
least in part, determines whether these adhesions turn over. For
example, once α-actinin is detected in these adhesions, they no
longer turn over, but tend to slide inward towards the cell body.
These studies indicate that the ordered recruitment of different
adhesion proteins may determine adhesion fate, for example,
turnover or maturation.
Regulators of adhesion turnover
The Rho family of small GTPases is a key regulator of adhesion
dynamics. In migrating cells, Rac is required for the formation of
new adhesions at the cell front, and Rho is required for the matu-
ration of existing contacts23. Rac may regulate adhesion turnover
either directly through downstream effectors and/or indirectly by
antagonizing Rho. The Rac effector PAK has been implicated in
focal adhesion disassembly50–52. Because PAK has several possible
targets, including myosin light-chain kinase (MLCK) and LIM
kinase (LIMK)53,54, both of which regulate cytoskeletal dynamics, it
is not yet clear how PAK influences adhesion stability.
Rho is involved in disassembly of adhesions at the rear of cells.
Rho and its effector, Rho kinase (p160ROCK), promote retraction
of the tail of migrating monocytes possibly by altering integrin
affinity and/or avidity55. Inhibition of Rho kinase or MLCK results
in elongation of cell tails consistent with Rho kinase and/or MLCK
NATURE CELL BIOLOGY VOL 4 APRIL 2002 http://cellbio.nature.com

being a positive effector of disassembly56. PAK activation is also
implicated, through its effects on contraction and detachment, in
retraction at the cell rear52,57.
Cells from knockout mice have implicated several molecules in
adhesion turnover. Fibroblasts from mice lacking FAK (FAK null
mice) have a reduced migration rate, a reduced rate of spreading,
and an increase in the number and size of peripherally localized
adhesions58. It has been suggested that the increase in peripheral
adhesions58,59 results from an inhibition of turnover in FAK−/− cells,
which may result from constitutive activation of Rho60. Expressing
wild-type FAK or mutant forms of FAK in FAK−/− cells shows that
the FAK autophosphorylation site (Tyr 397), its kinase activity, and
the first proline-rich SH3-binding region are all necessary for FAK-
enhanced migration61,62. Fibroblasts from mice lacking Src (Src
knockout mice) also show a decreased rate of spreading, and cells
deficient in three ubiquitously expressed family members, Src, Fyn
and Yes, have reduced motility63. Expressing kinase-defective
mutants of Src in normal fibroblasts results in enlarged, peripheral
adhesions64. Taken together, these studies imply that FAK and Src
are involved in adhesion turnover.
Even though the tyrosine kinases have received much of the
attention, tyrosine phosphatases are also implicated in adhesion
turnover. In neutophils, inhibition of Ca2+/calmodulin-activated
protein phosphatase 2B (calcineurin) prevented detachment of the
cells and decreased migration65. Fibroblasts deficient in the SHP-2
phosphatase have an increased number of adhesions and impaired
spreading and migration66. The phenotypes of SHP-2−/− and FAK−/−
are remarkably similar, suggesting that these molecules function to
modulate a common pathway in regulating cell migration and
adhesion dynamics. This hypothesis is supported by the observa-
tion that phosphorylation of FAK is increased in SHP-2−/− cells66.
Fibroblasts that lack protein tyrosine phosphatase (PTP)-PEST
have a serious migration defect and an increase in the number and
size of adhesions67. The migration defect seems to result at least in
part because of hyperphosphorylation of p130Cas, a PTP-PEST
substrate. Consistent with these results, Cas−/− fibroblasts have sig-
nificant defects in cell spreading and migration68. It is tempting to
speculate that adhesion turnover requires the coordinated cycling
of key regulators between a phosphorylated and dephosphorylated
states.
In addition to signalling components, calpain and microtubules
have been implicated in adhesion disassembly and turnover.
Calpain is a calcium-dependent protease that has several adhesion-
related substrates, including integrins, FAK and talin69. Cells treat-
ed with calpain inhibitors and calpain−/− fibroblasts have long tails,
inhibited migration, and large peripheral adhesions17,70–72.
Microtubules seem to promote disassembly of adhesions at the cell
rear by modulating contractility and delivering relaxing substances,
the nature of which are yet unclear3,74. When considering the mech-
anisms by which adhesions disassemble and turnover, the contribu-
tion of mechanical forces to these processes cannot be overlooked.
Theoretical models and current data indicate that contractile forces
may promote the release of adhesions at the cell rear by physically
rupturing weak or weakened molecular interactions1,17,47,75–79. Thus,
mechanical forces in conjunction with chemical modifications
probably drive adhesion disassembly.
Intracellular transport of adhesion molecules
A hallmark of a migrating cell is a pronounced polarity reflected in
a broad lamellipodium and often a pointed, retracting rear. The net
forward movement of cells over stable adhesions leads to an accu-
mulation of adhesion components towards the cell rear away from
the leading edge. In polarized, migrating cells, one anticipates that
mechanisms exist to move components from the cell rear toward
the cell front, where they are available to form new protrusions and
adhesions. Several mechanisms may transport integrins in this way.
Endocytic vesicles could move material directly from the rear to the
NATURE CELL BIOLOGY VOL 4 APRIL 2002 http://cellbio.nature.com
© 2002 Macmillan Magazines Ltd
review
front of the cell or the vesicles could traffic through an endosomal
recycling pathway.
Several studies have shown that integrin-containing vesicles
move from the rear of the cell to a perinuclear region37,45,46,65,80–82.
Additional evidence shows that integrin-containing vesicles move
from the perinuclear region to the base of the lamellipodium37 in
fibroblasts, and to an endosomal recycling compartment near the
cell front in neutrophils82. But vesicular transport of the integrins
from the cell rear to the leading edge has not been observed in
migrating fibroblasts, although such movement might be masked
by the high concentration of integrin-containing vesicles in the
perinuclear area17,45. Interestingly, integrin containing vesicles also
seem to move from the leading lamellipodia toward the perinuclear
region. Whether vesicles emanating from the front or rear are
degraded or recycled to the cell front remains to be addressed. In
addition, it is also not known whether recycling adhesion mole-
cules from the rear and/or the leading edge represents a significant
mechanism for supplying materials to the cell front. Other path-
ways, such as directed flow along cytoskeletal elements that target
substrate contact sites, may move various adhesion molecules to
the cell front83.
Emerging evidence indicates that signalling molecules are trans-
ported in complexes to and from functional regions of the cell by
way of a large, perinuclear cytoplasmic compartment. The ADP-
ribosylation factor (ARF) family of small GTPases and their GAPs
have been implicated in this process. The ARF-GAP protein p95-
APP1 enhances protrusion formation by a mechanism that
depends on Rac and ARF6 (ref. 84). p95APP1 localizes with Rac in
endosomal compartments suggesting that this ARF-GAP is
involved in delivering Rac to the plasma membrane84. The distribu-
tion of p95APP1 between the endosomal compartment and the
membrane is regulated by the ARF-GAP domain42. ARF1 is report-
ed to mediate paxillin recruitment from a perinuclear region to
adhesions85. PAG3, which is an ARF-GAP and paxillin binding pro-
tein, inhibits recruitment of paxillin to adhesions; but it is not clear
whether the GAP activity of this proteins is necessary for the
observed effect86.
GIT1, another ARF-GAP protein, cycles between adhesions, the
leading edge, and cytoplasmic complexes39. The cytoplasmic struc-
tures, which also contain paxillin, PAK and PIX, are not vesicular
but represent a multimolecular complex. GIT1 targets constitutive-
ly activated PAK to adhesions and the leading edge through its
interaction with paxillin. This suggests that these multimolecular
complexes can regulate the intracellular distribution of signalling
molecules, such as PAK, between adhesions, the cytoplasm, and the
leading edge of migrating cells. Whether the ARF-GAP activity of
GIT1 is involved in the targeting remains to be determined.
Conclusions
Cell migration is a complex, integrated process that requires the
continuous, coordinated formation and disassembly of adhesions.
Considerable progress has been made in identifying adhesion com-
ponents and the molecules that regulate these processes. The local-
ized activation and inactivation of these regulators and the mecha-
nisms by which they modulate the formation and breakdown of
adhesions are now key issues. How regulatory molecules influence
the addition or removal of adhesion components is emerging as a
pivotal issue. Recent imaging technologies are allowing adhesions
to be better characterized, on the basis of their molecular composi-
tion, organization, and dynamics; imaging technologies are also
providing assays for monitoring adhesion assembly/disassembly
during migration.
Finally, the mechanisms by which molecules are targeted to
forming adhesions and removed from dissolving adhesions is
another important challenge. Vesicular transport provides one
mechanism for these processes, but current evidence restricts this
pathway primarily to integrins and its relative contribution still
E99
review
needs to be established. Cytoskeletal-directed transport, including
microtubule-directed delivery, is another interesting mechanism.
Recent reports point to an additional mechanism of transport
through motile signalling complexes containing ARF-GAP mem-
bers, paxillin, PAK and PIX. These complexes seem to target differ-
ent locations where they may have distinct phenotypic effects.
At present, our understanding of adhesion assembly/disassem-
bly is limited. But the questions are defined, the pertinent technol-
ogy is in place, and the opportunities are considerable.
1. Lauffenburger, D. & Horwitz, A. Cell 84, 359–369 (1996).
2. Sells, M., Pfaff, A. & Chernoff, J. J. Cell Biol. 151, 1449–1458 (2000).
3. Kraynov, V. et al. Science 290, 333–337 (2000).
4. Sheetz, M. Semin. Cell Biol. 5, 149–155 (1994).
5. Lee, J., Ishihara, A., Theriot, J. & Jacobson, K. Nature 362, 167–171 (1993).
6. Wang, Y. J. Cell Biol. 101, 597–602 (1985).
7. Carson, M., Weber, A. & Zigmond, S. J. Cell Biol. 103, 2707–2714 (1986).
8. Borisy, G. & Svitkina, T. Curr. Opin. Cell Biol. 12, 104–112 (2000).
9. Burridge, K. & Chrzanowska-Wodnicka, M. Annu. Rev. Cell. Dev. Biol. 12, 463–518 (1996).
10. Miyamoto, S., Akiyama, S. & Yamada, K. Science 267, 883–885 (1995).
11. Yamada, K. & Miyamoto, S. Curr. Opin. Cell Biol. 7, 681–689 (1995).
12. Miyamoto, S. et al. J. Cell Biol. 131, 791–805 (1995).
13. Schoenwaelder, S. & Burridge, K. Curr. Opin. Cell Biol. 11, 274–286 (1999).
14. Beningo, K., Dembo, M., Kaverina, I., Small, J. & Wang, Y. J. Cell Biol. 153, 881–888 (2001).
15. Galbraith, C. & Sheetz, M. Proc. Natl Acad. Sci. USA 94, 9114–9118. (1997).
16. Lee, J., Leonard, M., Oliver, T., Ishihara, A. & Jacobson, K. J. Cell Biol. 127, 1957–1964 (1994).
17. Palecek, S., Huttenlocher, A., Horwitz, A. & Lauffenburger, D. J. Cell Sci. 111, 929–940 (1998).
18. Oliver, T., Dembo, M. & Jacobson, K. J. Cell Biol. 145, 589–604 (1999).
19. Zamir, E. & Geiger, B. J. Cell Sci. 114, 3583–3590 (2001).
20. Pankov, R. et al. J. Cell Biol. 148, 1075–1090 (2000).
21. Zamir, E. et al. Nature Cell Biol. 2, 191–197 (2000).
22. Nobes, C. & Hall, A. Cell 81, 53–62 (1995).
23. Rottner, K., Hall, A. & Small, J. Curr. Biol. 9, 640–648 (1999).
24. Lee, J. & Jacobson, K. J. Cell Sci. 110, 2833–2844 (1997).
25. Svitkina, T., Verkhovsky, A., McQuade, K. & Borisy, G. J. Cell Biol. 139, 397–415 (1997).
26. Chrzanowska-Wodnicka, M. & Burridge, K. J. Cell Biol. 133, 1403–1415 (1996).
27. Galbraith, C. & Sheetz, M. Curr. Opin. Cell Biol. 10, 566–571 (1998).
28. Sastry, S. & Burridge, K. Exp. Cell Res. 261, 25–36 (2000).
29. Balaban, N. et al. Nature Cell Biol. 3, 466–472 (2001).
30. Geiger, B. & Bershadsky, A. Curr. Opin. Cell Biol. 13, 584–592 (2001).
31. Small, J., Rottner, K., Kaverina, I. & Anderson, K. Biochim. Biophys. Acta 1404, 271–281 (1998).
32. Reinhard, M. et al. EMBO J. 11, 2063–2070 (1992).
33. Reinhard, M. et al. EMBO J. 14, 1583–1589 (1995).
34. Castellano, F., Le Clainche, C., Patin, D., Carlier, M. & Chavrier, P. EMBO J. 20, 5603–5614 (2001).
35. Machesky, L. et al. Biochem. J. 328, 105–112 (1997).
36. Rottner, K., Krause, M., Gimona, M., Small, J. & Wehland, J. Mol. Biol. Cell 12, 3103–3113 (2001).
37. Laukaitis, C., Webb, D., Donais, K. & Horwitz, A. J. Cell Biol. 153, 1427–1440 (2001).
38. Kiosses, W., Shattil, S., Pampori, N. & Schwartz, M. Nature Cell Biol. 3, 316–320 (2001).
E100
© 2002 Macmillan Magazines Ltd
39. Manabe, R., Kovalenko, M., Webb, D. & Horwitz, A. J. Cell Sci. in press (2002).
40. Knight, B. et al. Curr. Biol. 10, 576–585 (2000).
41. Yauch, R. et al. J. Exp. Med. 186, 1347–1355 (1997).
42. Matafora, V., Paris, S., Dariozzi, S. & de Curtis, I. J. Cell Sci. 114, 4509–4520 (2001).
43. DePasquale, J. A. & Izzard, C. S. J. Cell Biol. 105, 2803–2809 (1987).
44. Izzard, C. S. Cell Motil. Cytoskel. 10, 137–142 (1988).
45. Regen, C. & Horwitz, A. J. Cell Biol. 119, 1347–1359 (1992).
46. Palecek, S., Schmidt, C., Lauffenburger, D. & Horwitz, A. J. Cell Sci. 109, 941–952 (1996).
47. Crowley, E. & Horwitz, A. J. Cell Biol. 131, 525–537 (1995).
48. Smilenov, L., Mikhailov, A., Pelham, R., Marcantonio, E. & Gundersen, G. Science 286, 1172–1174
(1999).
49. Ballestrem, C., Hinz, B., Imhof, B. & Wehrle-Haller, B. J. Cell Biol. 155, 1319–1332 (2001).
50. Manser, E. et al. Mol. Cell Biol. 17, 1129–1143 (1997).
51. Frost, J., Khokhlatchev, A., Stippec, S., White, M. & Cobb, M. J. Biol. Chem. 273, 28191–28198
(1998).
52. Kiosses, W., Daniels, R., Otey, C., Bokoch, G. & Schwartz, M. J. Cell Biol. 147, 831–844 (1999).
53. Sanders, L., Matsumura, F., Bokoch, G. & de Lanerolle, P. Science 283, 2083–2085 (1999).
54. Edwards, D., Sanders, L., Bokoch, G. & Gill, G. Nature Cell Biol. 1, 253–259 (1999).
55. Worthylake, R., Lemoine, S., Watson, J. & Burridge, K. J. Cell Biol. 154, 147–160 (2001).
56. Somlyo, A. et al. Biochem. Biophys. Res. Commun. 269, 652–659 (2000).
57. Chung, C. & Firtel, R. J. Cell Biol. 147, 559–576 (1999).
58. Ilic, D. et al. Nature 377, 539–544 (1995).
59. Richardson, A., Malik, R., Heldebrand, J. & Parsons, J. Mol. Cell Biol. 17, 6906–6914 (1997).
60. Ren, X. et al. J. Cell Sci. 113, 3673–3678 (2000).
61. Sieg, D., Hauck, C. & Schlaepfer, D. J. Cell Sci. 112, 2677–2691 (1999).
62. Owen, J., Ruest, P., Fry, D. & Hanks, S. Mol. Cell Biol. 19, 4806–4818 (1999).
63. Klinghoffer, R., Sachsenmaier, C., Cooper, J. & Soriano, P. EMBO J. 18, 2459–2471 (1999).
64. Fincham, V. & Frame, M. EMBO J. 17, 81–92 (1998).
65. Lawson, M. & Maxfield, F. Nature 377, 75–79 (1995).
66. Yu, D.-H., Qu, C.-K., Henegariu, O., Lu, X. & Feng, G.-S. J. Biol. Chem. 273, 21125–21131 (1998).
67. Angers-Loustau, A. et al. J. Cell Biol. 144, 1019–1031 (1999).
68. Honda, H., Nakamoto, T., Sakai, R. & Hirai, H. Biochem. Biophys. Res. Commun. 262, 25–30 (1999).
69. Cox, E. & Huttenlocher, A. Microsc. Res. Tech. 43, 412–419 (1998).
70. Huttenlocher, A. et al. J. Biol. Chem. 272, 32719–32722 (1997).
71. Glading, A., Chang, P., Lauffenburger, D. & Wells, A. J. Biol. Chem. 275, 2390–2398 (2000).
72. Dourdin, N. et al. J. Biol. Chem. 276, 48382–48388 (2001).
73. Kaverina, I., Krylyshkina, O. & Small, J. J. Cell Biol. 146, 1033–1043 (1999).
74. Kaverina, I. et al. Curr. Biol. 10, 739–742 (2000).
75. Wilson, A., Gorgas, G., Claypool, W. & de Lanerolle, P. J. Cell Biol. 114, 277–283 (1991).
76. Kuo, S. & Lauffenburger, D. Biophys. J. 65, 2191–2200 (1993).
77. Jay, P., Pham, P., Wong, S. & Elson, E. J. Cell Sci. 108, 387–393 (1995).
78. Saterbak, A. & Lauffenburger, D. A. Biotechnol. Prog. 12, 682–699 (1996).
79. Evans, E. & Ritchie, K. Biophys. J. 72, 1541–1555 (1997).
80. Bretscher, M. & Aguado-Velasco, C. Curr. Opin. Cell Biol. 10, 537–541 (1998).
81. Bretscher, M. Science 224, 681–686 (1984).
82. Pierini, L., Lawson, M., Eddy, R., Hendey, B. & Maxfield, F. Blood 95, 2471–2480 (2000).
83. Kaverina, I., Rottner, K. & Small, J. J. Cell Biol. 142, 181–190 (1998).
84. Di Cesare, A. et al. Nature Cell Biol. 2, 521–530 (2000).
85. Norman, J. et al. J. Cell Biol. 143, 1981–1995 (1998).
86. Kondo, A. et al. Mol. Biol. Cell 11, 1315–1327 (2000).
NATURE CELL BIOLOGY VOL 4 APRIL 2002 http://cellbio.nature.com