PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Curr Opin Cell Biol. Author manuscript; available in PMC 2011 October 1.
Published in final edited form as:
PMCID: PMC2948584
NIHMSID: NIHMS226033

Conserved F-actin Dynamics and Force Transmission at Cell Adhesions

Abstract/Summary

Adhesions are a central mechanism by which cells mechanically interact with the surrounding extracellular matrix (ECM) and neighboring cells. In both cell-ECM and cell-cell adhesions, forces generated within the actin cytoskeleton are transmitted to the surrounding environment and are essential for numerous morphogenic processes. Despite differences in many molecular components that regulate cell-cell and cell-ECM adhesions, the roles of F-actin dynamics and mechanical forces in adhesion regulation are surprisingly similar. Moreover, force transmission at adhesions occurs concomitantly with dynamic F-actin; proteins comprising the adhesion of F-actin to the plasma membrane must accommodate this movement while still facilitating force transmission. Thus, despite different molecular architectures, integrin and cadherin-mediated adhesions operate with common biophysical characteristics to transmit and respond to mechanical forces in a multicellular tissue.

Introduction

Cellular adhesion to the surrounding extracellular environment is essential to numerous aspects of cell and tissue physiology. The dynamic regulation of adhesions to extracellular matrix (ECM) is crucial to cell proliferation, differentiation and migration [1,2] while adhesions formed between neighboring cells mediate sorting, rearrangement and polarization within multicellular ensembles [3]. The coordination of cell-ECM and cell-cell adhesions is essential for the formation, regulation and maintenance of tissues. These morphological and physical processes all require precise spatiotemporal regulation of force transmission at adhesions that can rapidly adapt and respond to internal or external physical and biochemical stimuli.

Adhesions are not simply sites of passive mechanical attachment; rather, forces generated within the F-actin cytoskeleton generate active tension that is applied to cellular adhesions. Both the F-actin cytoskeleton and proteins comprising adhesions are highly dynamic, providing the capability to build, maintain and release tension at adhesion sites over physiological time scales. Thus, this dynamic and responsive force transmission is essential for cellular and tissue physiology, but the underlying biophysical mechanisms remain unclear. While significant differences in the molecular composition of cell-cell and cell-ECM adhesions exist, it has recently become evident that these two types of adhesions share remarkable similarities in the nature of mechanoresponsiveness and local cytoskeletal dynamics. Here, we review current understanding of the role of F-actin dynamics and forces in the regulation of integrin-mediated cell-ECM adhesion and cadherin-mediated cell-cell adhesion. We also discuss current data and models for the mechanisms of force transmission through a dynamic cytoskeleton at adhesion sites.

Forces at cell-ECM and cell-cell contacts

The primary sites of force transmission between the cell and the extracellular matrix occur at integrin-mediated adhesions (Fig. 1A). Such cellular traction forces can be visualized by adhering cells to compliant, calibrated substrates and visualizing the deformations induced by the cell’s substrate-contacting, or basal, surface [4,5]. Cellular traction forces are primarily concentrated at peripheral focal adhesions, directed towards the cell center and are as large as several nano-Newtons [4,5]. In quiescent cells, there is a direct correlation between focal adhesion size and traction force magnitude [4-6], and a feedback between adhesion size and either myosin-II driven or externally applied force exists [7]. Indeed, application of force leads to enhanced stiffening and force transmission at focal adhesion sites and is required for stabilization of new adhesive contacts [8,9].

Figure 1
Molecular composition of cadherin-based cell-cell contacts and focal adhesions. (A) Immunofluorescence image of two adjoining MDCK cells plated on collagen I, with F-actin stained by phalloidin (green), focal adhesions marked by paxillin (red), and cell-cell ...

Similar to focal adhesions, classic cadherin-based adhesions act as force-sensitive and force-bearing mechanical links to maintain cell-cell contact [10] (Fig. 1A). However, it has been difficult to measure the forces sustained at bonafide cell-cell contacts due to the relative inaccessibility to the interface [11]. Laser ablation of cytoskeletal components at cell-cell contacts provides an estimate of the relative magnitude of force sustained [12]; forces at cadherin-mediated adhesions appear to be tensile and directed either parallel or normal to the plane of cell-cell contact [13]. Tensile forces transmitted at cell-cell contacts determine cellular arrangements within a monolayer [12,14-16] and direct collective migration of epithelial cells [17]. Quantitative measurements of forces generated at cadherin-based adhesions have been made with cells adhered to compliant, cadherin-coated substrates wherein cadherin-mediated adhesions form on the cell’s basal surface, akin to focal adhesions in 2D culture. Interestingly, the organization, direction and magnitude of traction forces exerted by N-cadherin-mediated adhesions are strikingly similar to those transmitted at focal adhesions [18,19]. Moreover, similar to focal adhesions, the assembly and stabilization of cadherin-mediated adhesions is force dependent [19-21]. Thus, both cadherin and integrin-based adhesions are mechanosensitive assemblies that transmit significant mechanical cues between a cell and its external environment [10].

Physical link between F-actin and adhesion receptors

The assembly of integrin-mediated adhesions occurs concomitantly with force-dependent compositional changes and post-translational modifications in a process termed maturation [8,9]. These changes are thought to both enhance mechanical coupling between the F-actin and extracellular matrix and regulate the cycle of adhesion assembly/disassembly (Fig. 1B). Under low tension, labile connections between F-actin and transmembrane integrin are formed by talin [22]. In turn, talin binding induces conformational changes in integrin to enhance binding to the ECM [23,24]. Force applied to this linkage results in clustering and activation of more integrins [25] and recruitment and phosphorylation of focal adhesion kinase (FAK) [26], which initiates integrin-mediated signaling and phosphorylation of other focal adhesion proteins, including paxillin and p130cas [27]. Subsequent recruitment of vinculin likely reinforces the mechanical linkage between F-actin and transmembrane integrin [9]. These signaling and compositional changes are associated with focal adhesion growth from a sub-micron cluster into an elongated plaque and are accompanied by the recruitment of α-actinin and zyxin, promoting further association with F-actin [9]. Thus, in cell-ECM adhesions, a hierarchical assembly of structural and signal proteins are utilize to regulate mechanical attachment between the F-actin and ECM.

The structural links that associate F-actin to transmembrane cadherins is less clear, although not due to lack of candidates (Fig. 1B). While the proximal region of the cytoplasmic domain of cadherin binds to p120-catenin, the distal region binds to β-catenin or plakoglobin, which in turn binds to α-catenin. The linkage between α-catenin and F-actin can be mediated by numerous proteins [28,29] such as: vinculin, formin [30], α-actinin , eplin [31], afadin [28,29] and ZO-1 . Vinculin may also directly bind to β-catenin [32], but may remain auto-inhibited [33]. Even though multiple links may co-exist, some of the linkers may not simultaneously function due to steric or allosteric effects. Delineating which of these different putative links play functional roles in different cells and physiological contexts will be required to better understand the mechanical regulation of cadherin adhesions by F-actin.

Regulation of adhesions by F-actin dynamics

Throughout their lifecycle, focal adhesions are associated with a dynamic actin cytoskeleton. The assembly of focal adhesions occurs within a branched F-actin meshwork near the cell periphery, termed the lamellipodium, which undergoes a rapid retrograde flow, approximately 25 nm/s, driven by F-actin polymerization against the cell membrane [34] (Fig. 2). Here, focal adhesion clusters form and flow retrograde with F-actin to the lamellipodial base, 1-3 μm proximally from the cell edge, where they immobilize and become small, sub-micron-sized punctae termed nascent adhesions [34-37]. Nascent adhesions are associated with low traction (~ 150 pN) exerted on the ECM and F-actin flow on the order 15-25 nm/s; here, the F-actin dynamics and traction originate from F-actin polymerization-generated forces [38]. Myosin II-mediated tension applied to F-actin at the lamellipodia base promotes force-dependent focal adhesion maturation [8,9]. Mature focal adhesions are associated with myosin II rich networks or bundles and transmit large traction forces (1-5 nN). Here, myosin II-mediated retrograde actin flow persists at focal adhesions but is generally on the order of 5-10 nm/s [38,39] (Fig. 2). VASP, a regulator of F-actin polymerization dynamics, localizes to focal adhesions [27] and can undergo retrograde motion similar to that of actin [40]. Formindependent polymerization of F-actin plays a crucial role in myosin-dependent stress fiber elongation and force-dependent focal adhesion growth [4,41].

Figure 2
F-actin dynamics in nascent and mature adhesions. (top, NASCENT) In both focal adhesions and cell-cell adhesions, adhesion assembly occurs near the cell periphery within the lamellipodium, a zone of rapid, polymerization-driven F-actin retrograde flow ...

Similar to focal adhesions, cadherin-based adhesions also form at lamellipodia or at filopodia, where cells initiate contact [42-44] (Fig. 2). E-cadherin adhesions initiate as sub-micron sized puncta, but grow into elongated plaques [42], dependent on local and global actin motion [45]. In well-developed contacts, there is no F-actin retrograde flow perpendicular to cell-cell contacts [46]. However, there is considerable F-actin motion within the plane of the cell-cell contact [47], wherein myosin-II dependent basal to apical movement of cadherin clusters and associated actin is observed at a rate of 5 nm/s (Fig. 2). Two distinct populations of actin are associated with E-cadherin clusters: a stable pool that is localized with the clusters and a contractile, dynamic pool that controls the position of the clusters [48,49]. Several actin binding and regulatory proteins such as myosin VI, Arp 2/3, ena/VASP and cortactin are necessary for proper junction formation [43,44,50]. Disparate dynamics of the cadherin-catenin complex and actin at cell-cell contacts also suggests dynamic coupling between F-actin and cadherin [33]. The overall architecture of F-actin at sites of cell-cell contact, however, depends on the cell type and may even vary between different epithelial cell lines [51]. Cells plated on N-cadherin coated coverslips form cadherin-mediated adhesions at the cell periphery near the lamellipodia. After appearance, cadherin-mediate adhesions elongate in a myosin-dependent manner and are associated with dynamic actin [52]. Thus, several similar features of F-actin dynamics regulate the assembly and growth of both cadherin and integrin-based adhesions, in spite of differences in structural links.

How can a dynamic cytoskeleton sustain mechanical load?

Forces generated by myosin II motors and F-actin polymerization drive coherent movements of the actin cytoskeleton. To reconcile how adhesions harness such actin dynamics to mediate force transmission to the extracellular environment, it has long been hypothesized that adhesions function as a “molecular clutch” between the F-actin cytoskeleton and extracellular ligands [53]. In this model, retrograde F-actin flow is treated as an ‘engine’ running at a certain speed with a certain stall force. When an adhesion is assembled to engage the F-actin to extracellular ligands, resistive forces from the extracellular matrix stall F-actin movement. In models of cell migration, this ‘stalled’ retrograde motion, corresponding to a high tension state, would then enable de novo assembly of F-actin at the cell front to result in efficient cell protrusion. Indeed, observed inverse correlations between protrusion rate and F-actin retrograde flow in fast moving cells support this model [54,55].

The most natural way to conceptualize a molecular clutch would be for it to be a binary switch, either “on/engaged” or “off/disengaged”. However, recent data have shown that this simplistic picture does not accommodate the rich interplay between cytoskeletal dynamics and traction forces at adhesion sites. For instance, during focal adhesion assembly in epithelial and fibroblast cells, increased traction stress occurs concomitantly with decreased F-actin retrograde flow speed [37,38] (Fig. 3); thus, a continuous transition between an “off” and an “on” state exists. Furthermore, in focal adhesions that exert high tension on the ECM, retrograde flow of F-actin persists. In other words, a fully engaged clutch must accommodate F-actin motion while still transmitting tension. Similar dynamic links between N-cadherin mediated adhesions to moving F-actin are also likely [56].

Figure 3
The correlation between F-actin and traction force during adhesion assembly in the lamellipodium (LP) and in stable adhesions found in the lamella (LM). In the lamellipodium, F-actin polymerization drives a rapid retrograde flow. During adhesion assembly ...

One possibility is that transient connections between proteins within adhesions could foster a dynamic molecular clutch [57]. For example, vinculin, α-actinin, zyxin, VASP and talin undergo retrograde flux correlated to the actin motion at large focal adhesions [39,40,58] . On the other hand, integrin, FAK and paxillin are predominantly stationary with respect to the ECM over similar time-scales. Force transmission through such a dynamic interface can be modeled by considering a population of dynamic bonds formed between a moving and stationary interface with individual bonds undergoing cycles of attachment and force-assisted detachment. Thus, the dynamics of bond association/dissociation facilitate F-actin motion and force transmission simultaneously [57,59-61]. These models are consistent with the observed relationships between F-actin flow speed and traction force [60,61]; at high retrograde flow rates, force transmission is limited by bond breakage whereas at low rates, the magnitude of displacement or force within the actin cytoskeleton is limiting. Furthermore, these models have elucidated how such a dynamic clutch could facilitate adhesion assembly [59] and mechanosensing [57]. This mechanism allows for both the build-up of tension at locations of rapid F-actin flow to promote adhesion assembly and reduce tension at sites of low F-actin flow to promote adhesion disassembly.

The role of F-actin dynamics in regulating force transmission in mature focal adhesions is less well understood. In some cell types, where adhesions are associated with contractile actomyosin networks, traction forces diminish as the F-actin flow speed decreases below a critical threshold [38,57,62] (Fig. 3). This direct correlation is consistent with the picture that retrograde movement of F-actin is a manifestation of myosin forces and diminished rates of F-actin movement is an indicator of reduced myosin II force. Alternatively, in cells that form organized stress fibers, forces exerted at focal adhesions can be modulated significantly without changes in retrograde flow speed (Fig. 3). Thus, at large adhesions, local organization of F-actin may dominate over F-actin dynamics in determining the magnitude of force transmitted. While F-actin dynamics and organization are likely to play similar roles in force transmission at cadherin-based adhesions, their roles are much less clear.

In conclusion, there exists a strong interdependence between F-actin dynamics, adhesion assembly and force transmission occurring at both cell-ECM and cell-cell adhesions despite dramatic differences in the molecular components that link F-actin to extracellular ligands in these two different types of cell adhesions. This suggests that the origins of cellular mechanoresponsiveness may be dominated by generic physical features of the actin cytoskeleton coupled to a dynamic clutch rather than specific molecular components of adhesions. Moreover, the generality of these behaviors to two very different types of cell adhesions suggests that there may be common underlying physical principles relating adhesion assembly, actin dynamics and force transmission. Elucidating such general physical principles will enable predictive understanding of the nature of adaptive force transduction in the cytoskeleton and its transmission to the external environment that facilitates complex processes such as cell migration and multi-cellular organization.

Acknowledgements

MLG would like to acknowledge funding from a Burroughs Welcome Career Award at the Scientific Interface and NIH DP10D00354.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

1. Berrier AL, Yamada KM. Cell-matrix adhesion. J Cell Physiol. 2007;213:565–573. [PubMed]
2. Rozario T, DeSimone DW. The extracellular matrix in development and morphogenesis: A dynamic view. Developmental Biology. 2010;341:126–140. [PMC free article] [PubMed]
3. Borghi N, James Nelson W, Thomas L. Chapter 1 Intercellular Adhesion in Morphogenesis: Molecular and Biophysical Considerations. In: Academic Press, editor. Current Topics in Developmental Biology. Volume 89. 2009. pp. 1–32. [PubMed]
4. Balaban NQ, Schwarz US, Riveline D, Goichberg P, Tzur G, Sabanay I, Mahalu D, Safran S, Bershadsky A, Addadi L, et al. Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates. Nat Cell Biol. 2001;3:466–472. [PubMed]
5. Tan JL, Tien J, Pirone DM, Gray DS, Bhadriraju K, Chen CS. Cells lying on a bed of microneedles: an approach to isolate mechanical force. Proc Natl Acad Sci U S A. 2003;100:1484–1489. [PubMed]
6. Goffin JM, Pittet P, Csucs G, Lussi JW, Meister JJ, Hinz B. Focal adhesion size controls tension-dependent recruitment of alpha-smooth muscle actin to stress fibers. J Cell Biol. 2006;172:259–268. [PMC free article] [PubMed]
*7. Riveline D, Zamir E, Balaban NQ, Schwarz US, Ishizaki T, Narumiya S, Kam Z, Geiger B, Bershadsky AD Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism. J Cell Biol. 2001;153:1175–1186. [PubMed]
*First to identify force-dependent growth fo focal adhesions
*8. Geiger B, Spatz JP, Bershadsky AD Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol. 2009;10:21–33. [PubMed]
*Review of the role of focal adhesions in environmental sensing.
*9. Vicente-Manzanares M, Choi CK, Horwitz AR Integrins in cell migration-the actin connection. J Cell Sci. 2009;122:1473. [PubMed]
*Recent review of the role of actin dynamics in focal adhesion assembly
*10. Schwartz MA, DeSimone DW Cell adhesion receptors in mechanotransduction. Curr Opin Cell Biol. 2008;20:551–556. [PubMed]
*Review of the role of integrins and cadherins in mechanotransduction
11. Brevier J, Vallade M, Riveline D. Force-Extension Relationship of Cell-Cell Contacts. Physical Review Letters. 2007;98:268101. [PubMed]
*12. Rauzi M, Verant P, Lecuit T, Lenne P-F Nature and anisotropy of cortical forces orienting Drosophila tissue morphogenesis. Nat Cell Biol. 2008;10:1401–1410. [PubMed]
*Measurement of anisotropic forces during tissue morphogenesis
13. Cavey M, Lecuit T. Molecular Bases of Cell-Cell Junctions Stability and Dynamics. Cold Spring Harbor Perspectives in Biology. 2009;1:a002998. [PMC free article] [PubMed]
14. Farhadifar R, Röper J-C, Aigouy B, Eaton S, Jülicher F. The Influence of Cell Mechanics, Cell-Cell Interactions, and Proliferation on Epithelial Packing. Current Biology. 2007;17:2095–2104. [PubMed]
15. Kafer J, Hayashi T, Marée AFM, Carthew RW, Graner Fo. Cell adhesion and cortex contractility determine cell patterning in the Drosophilaretina. Proceedings of the National Academy of Sciences. 2007;104:18549–18554. [PubMed]
16. Fernandez-Gonzalez R, Sde M Simoes, Roper JC, Eaton S, Zallen JA. Myosin II dynamics are regulated by tension in intercalating cells. Dev Cell. 2009;17:736–743. [PMC free article] [PubMed]
17. Trepat X, Wasserman MR, Angelini TE, Millet E, Weitz DA, Butler JP, Fredberg JJ. Physical forces during collective cell migration. Nat Phys. 2009;5:426–430.
18. Ganz A, Lambert M, Saez A, Silberzan P, Buguin A, Mège RM, Ladoux Bt. Traction forces exerted through N-cadherin contacts. Biol. Cell. 2006;98:721–730. [PubMed]
*19. Ladoux B, Anon E, Lambert M, Rabodzey A, Hersen P, Buguin A, Silberzan P, Mège R-M Strength Dependence of Cadherin-Mediated Adhesions. Biophysical Journal. 2010;98:534–542. [PubMed]
*Demonstrated force-dependent strengthening of cadherin-mediated adhesion
20. Shewan AM, Maddugoda M, Kraemer A, Stehbens SJ, Verma S, Kovacs EM, Yap AS. Myosin 2 Is a Key Rho Kinase Target Necessary for the Local Concentration of E-Cadherin at Cell-Cell Contacts. Mol. Biol. Cell. 2005;16:4531–4542. [PMC free article] [PubMed]
21. Kris AS, Kamm RD, Sieminski AL. VASP involvement in force-mediated adherens junction strengthening. Biochemical and Biophysical Research Communications. 2008;375:134–138. [PMC free article] [PubMed]
22. Jiang G, Giannone G, Critchley DR, Fukumoto E, Sheetz MP. Two-piconewton slip bond between fibronectin and the cytoskeleton depends on talin. Nature. 2003;424:334–337. [PubMed]
23. Calderwood DA, Zent R, Grant R, Rees DJ, Hynes RO, Ginsberg MH. The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation. J Biol Chem. 1999;274:28071–28074. [PubMed]
*24. Puklin-Faucher E, Sheetz MP The mechanical integrin cycle. J Cell Sci. 2009;122:179–186. [PubMed]
*Review of the mechanics during focal adhesion assembly and maturation.
*25. Roca-Cusachs P, Gauthier NC, del Rio A, Sheetz MP Clustering of alpha5beta1 integrins determines adhesion strength whereas alphavbeta3 and talin enable mechanotransduction. Proceedings of the National Academy of Sciences. 2009;106:16245–16250. [PubMed]
*Identification of Integrin-dependent roles in adhesion strength and mechanotransduction.
26. Friedland JC, Lee MH, Boettiger D. Mechanically activated integrin switch controls alpha5beta1 function. Science. 2009;323:642–644. [PubMed]
27. Zaidel-Bar R, Itzkovitz S, Ma’ayan A, Iyengar R, Geiger B. Functional atlas of the integrin adhesome. Nat Cell Biol. 2007;9:858–867. [PMC free article] [PubMed]
*28. Miyoshi J, Takai Y Structural and functional associations of apical junctions with cytoskeleton. Biochimica et Biophysica Acta (BBA) - Biomembranes. 2008;1778:670–691. [PubMed]
* Review of the molecular components of cadherin-based adhesion.
29. Sawyer JK, Harris NJ, Slep KC, Gaul U, Peifer M. The Drosophila afadin homologue Canoe regulates linkage of the actin cytoskeleton to adherens junctions during apical constriction. The Journal of Cell Biology. 2009;186:57–73. [PMC free article] [PubMed]
30. Carramusa L, Ballestrem C, Zilberman Y, Bershadsky AD. Mammalian diaphanous-related formin Dia1 controls the organization of E-cadherin-mediated cell-cell junctions. J Cell Sci. 2007;120:3870–3882. [PubMed]
31. Abe K, Takeichi M. EPLIN mediates linkage of the cadherin—catenin complex to F-actin and stabilizes the circumferential actin belt. Proceedings of the National Academy of Sciences. 2008;105:13–19. [PubMed]
32. Peng X, Cuff LE, Lawton CD, DeMali KA. Vinculin regulates cell-surface E-cadherin expression by binding to {beta}-catenin. J Cell Sci. 2010;123:567–577. [PubMed]
33. Yamada S, Pokutta S, Drees F, Weis WI, Nelson WJ. Deconstructing the Cadherin-Catenin-Actin Complex. Cell. 2005;123:889–901. [PMC free article] [PubMed]
*34. Choi CK, Vicente-Manzanares M, Zareno J, Whitmore LA, Mogilner A, Horwitz AR Actin and alpha-actinin orchestrate the assembly and maturation of nascent adhesions in a myosin II motor-independent manner. Nat Cell Biol. 2008;10:1039–1050. [PubMed]
*Demonstrated mechanism of myosin II independent maturation of focal adhesions.
35. Wiseman PW, Brown CM, Webb DJ, Hebert B, Johnson NL, Squier JA, Ellisman MH, Horwitz AF. Spatial mapping of integrin interactions and dynamics during cell migration by image correlation microscopy. J Cell Sci. 2004;117:5521–5534. [PubMed]
36. Galbraith CG, Yamada KM, Galbraith JA. Polymerizing actin fibers position integrins primed to probe for adhesion sites. Science. 2007;315:992–995. [PubMed]
37. Aratyn-Schaus Y, Gardel ML. Transient Frictional Slip between Integrin and the ECM in Focal Adhesions under Myosin II Tension. Curr Biol. 2010;20:1145–1153. [PMC free article] [PubMed]
*38. Gardel ML, Sabass B, Ji L, Danuser G, Schwarz US, Waterman CM Traction stress in focal adhesions correlates biphasically with actin retrograde flow speed. J Cell Biol. 2008;183:999–1005. [PubMed]
*Characterized the relationship between traction stresses and F-actin dynamics at focal adhesions.
*39. Hu K, Ji L, Applegate KT, Danuser G, Waterman-Storer CM Differential transmission of actin motion within focal adhesions. Science. 2007;315:111–115. [PubMed]
*Characterized differential motion of focal adhesion proteins within adhesions.
40. Guo W-h, Wang Y-l. Retrograde Fluxes of Focal Adhesion Proteins in Response to Cell Migration and Mechanical Signals. Mol. Biol. Cell. 2007;18:4519–4527. [PMC free article] [PubMed]
41. Hotulainen P, Lappalainen P. Stress fibers are generated by two distinct actin assembly mechanisms in motile cells. J Cell Biol. 2006;173:383–394. [PMC free article] [PubMed]
42. Adams CL, Chen Y-T, Smith SJ, Nelson W James. Mechanisms of Epithelial Cell-Cell Adhesion and Cell Compaction Revealed by High-resolution Tracking of E-Cadherin-Green Fluorescent Protein. The Journal of Cell Biology. 1998;142:1105–1119. [PMC free article] [PubMed]
43. Vasioukhin V, Bauer C, Yin M, Fuchs E. Directed Actin Polymerization Is the Driving Force for Epithelial Cell-Cell Adhesion. Cell. 2000;100:209–219. [PubMed]
44. Mège R-M, Gavard J, Lambert M. Regulation of cell-cell junctions by the cytoskeleton. Current Opinion in Cell Biology. 2006;18:541–548. [PubMed]
45. Yamada S, Nelson WJ. Localized zones of Rho and Rac activities drive initiation and expansion of epithelial cell cell adhesion. J. Cell Biol. 2007;178:517–527. [PMC free article] [PubMed]
46. Waterman-Storer CM, Salmon WC, Salmon ED. Feedback Interactions between Cell-Cell Adherens Junctions and Cytoskeletal Dynamics in Newt Lung Epithelial Cells. Mol. Biol. Cell. 2000;11:2471–2483. [PMC free article] [PubMed]
*47. Kametani Y, Takeichi M Basal-to-apical cadherin flow at cell junctions. Nat Cell Biol. 2007;9:92–98. [PubMed]
*Demonstrated basal to apical flow of cadherin-based adhesion.
48. Zhang J, Betson M, Erasmus J, Zeikos K, Bailly M, Cramer LP, Braga VMM. Actin at cell-cell junctions is composed of two dynamic and functional populations. J Cell Sci. 2005;118:5549–5562. [PubMed]
*49. Cavey M, Rauzi M, Lenne P-F, Lecuit T A two-tiered mechanism for stabilization and immobilization of E-cadherin. Nature. 2008;453:751–756. [PubMed]
*Identified the role of actin dynamics in stabilization of e-cadherin.
50. Maddugoda MP, Crampton MS, Shewan AM, Yap AS. Myosin VI and vinculin cooperate during the morphogenesis of cadherin cell—cell contacts in mammalian epithelial cells. The Journal of Cell Biology. 2007;178:529–540. [PMC free article] [PubMed]
51. Meng W, Takeichi M. Adherens Junction: Molecular Architecture and Regulation. Cold Spring Harbor Perspectives in Biology. 2009;1:a002899. [PMC free article] [PubMed]
52. Lambert M, Thoumine O, Brevier J, Choquet D, Riveline D, Mège R-M. Nucleation and growth of cadherin adhesions. Experimental Cell Research. 2007;313:4025–4040. [PubMed]
53. Mitchison T, Kirschner M. Cytoskeletal dynamics and nerve growth. Neuron. 1988;1:761–772. [PubMed]
54. Lin CH, Forscher P. Growth cone advance is inversely proportional to retrograde F-actin flow. Neuron. 1995;14:763–771. [PubMed]
55. Jurado C, Haserick JR, Lee J. Slipping or gripping? Fluorescent speckle microscopy in fish keratocytes reveals two different mechanisms for generating a retrograde flow of actin. Mol Biol Cell. 2005;16:507–518. [PMC free article] [PubMed]
*56. Bard L, Boscher C, Lambert M, Mege R-M, Choquet D, Thoumine O A Molecular Clutch between the Actin Flow and N-Cadherin Adhesions Drives Growth Cone Migration. J. Neurosci. 2008;28:5879–5890. [PubMed]
*Identified molecular clutch between F-actin and N-cadherin mediated adhesion
57. Chan CE, Odde DJ Traction dynamics of filopodia on compliant substrates. Science. 2008;322:1687–1691. [PubMed]
*Identified the role of a F-actin dynamics at focal adhesions in mechanosensation.
*58. Brown CM, Hebert B, Kolin DL, Zareno J, Whitmore L, Horwitz AR, Wiseman PW Probing the integrin-actin linkage using high-resolution protein velocity mapping. J Cell Sci. 2006;119:5204–5214. [PubMed]
*Observed differential motion of focal adhesion proteins with focal adhesions
59. Macdonald A, Horwitz AR, Lauffenburger DA. Kinetic model for lamellipodal actin-integrin ‘clutch’ dynamics. Cell Adh Migr. 2008;2:95–105. [PMC free article] [PubMed]
60. Li Y, Bhimalapuram P, Dinner AR. Model for how retrograde actin flow regulates adhesion traction stresses. Journal of Physics: Condensed Matter. 2010;22:194113. [PubMed]
61. Sabass B, Schwarz U,S. Modeling cytoskeletal flow over adhesion sites: competition between stochastic bond dynamics and intracellular relaxation. Journal of Physics: Condensed Matter. 2010;22:194112. [PubMed]
62. Fournier MF, Sauser R, Ambrosi D, Meister J-J, Verkhovsky AB. Force transmission in migrating cells. The Journal of Cell Biology. 188:287–297. [PMC free article] [PubMed]
63. Miyoshi J, Takai Y. Structural and functional associations of apical junctions with cytoskeleton. Biochim Biophys Acta. 2008;1778:670–691. [PubMed]