Focal Adhesion Motility Revealed in Stationary Fibroblasts

Smilenov, Lubomir B.; Mikhailov, Alexei; Pelham, Robert J.; Marcantonio, Eugene E.; Gundersen, Gregg G.

doi:10.1126/science.286.5442.1172

Cited by 319 publications

(287 citation statements)

References 16 publications

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“…The mechanism will provide the strongest propulsive forces for slow-moving cells on stiff substrates, which are known to induce strong resistive adhesions as well as traction forces (Guo et al, 2006). A second potential function of a regulated flux at focal adhesions is to serve as a slippage clutch for cell migration (Smilenov et al, 1999;Hu et al, 2007). Retrograde flux may reflect disengagement of the clutch, when contractile forces are consumed in the transport of actin filaments rather than transmitted to the substrate for cell migration.…”

Section: Discussionmentioning

confidence: 99%

Retrograde Fluxes of Focal Adhesion Proteins in Response to Cell Migration and Mechanical Signals

Guo

Wang

2007

MBoC

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Recent studies suggest that mechanical signals mediated by the extracellular matrix play an essential role in various physiological and pathological processes; yet, how cells respond to mechanical stimuli remains elusive. Using live cell fluorescence imaging, we found that actin filaments, in association with a number of focal adhesion proteins, including zyxin and vasodilator-stimulated phosphoprotein, undergo retrograde fluxes at focal adhesions in the lamella region. This flux is inversely related to cell migration, such that it is amplified in fibroblasts immobilized on micropatterned islands. In addition, the flux is regulated by mechanical signals, including stretching forces applied to flexible substrates and substrate stiffness. Conditions favoring the flux share the common feature of causing large retrograde displacements of the interior actin cytoskeleton relative to the substrate anchorage site, which may function as a switch translating mechanical input into chemical signals, such as tyrosine phosphorylation. In turn, the stimulation of actin flux at focal adhesions may function as part of a feedback mechanism, regulating structural assembly and force production in relation to cell migration and mechanical load. The retrograde transport of associated focal adhesion proteins may play additional roles in delivering signals from focal adhesions to the interior of the cell. INTRODUCTIONRecent studies suggest that mechanosensing is involved in several physiological processes, including embryogenesis (Newman and Comper, 1990;Beloussov et al., 1994) and wound healing (Hinz et al., 2001;Tomasek et al., 2002), and in pathological processes such as fibrosis and carcinogenesis (Paszek et al., 2005). Adherent cells seem capable of both responding to applied mechanical forces (Tzima et al., 2005) and applying contractile forces to probe mechanical properties of the environment (Discher et al., 2005). The downstream responses include changes in migration (Pelham and Wang, 1997;Sheetz et al., 1998;Lo et al., 2000), cell-cell interactions (Guo et al., 2006), proliferation (Wang et al., 2000Nelson et al., 2005), differentiation (Engler et al., 2004(Engler et al., , 2006, and apoptosis . For cultured adherent cells, focal adhesions are thought to mediate mechanosensing through integrin-mediated anchorage to the extracellular matrix (Larsen et al., 2006). The molecular repertoire of focal adhesions includes Ͼ100 adaptor and signaling proteins (Bershadsky et al., 2006), in addition to associated actomyosin bundles that provide mechanical forces for probing the environment (Choquet et al., 1997), inside-out signaling (Chrzanowska-Wodnicka and Burridge, 1996;Schwartz and Ginsberg, 2002), and cell migration (Ridley et al., 2003). However, few details are available concerning how these components work in concert to generate the responses to mechanical signals.Several aspects have emerged recently as the key features of integrin-mediated mechanosensing. First is the increase in cortical organization and contractility in resp...

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Section: Discussionmentioning

confidence: 99%

Retrograde Fluxes of Focal Adhesion Proteins in Response to Cell Migration and Mechanical Signals

Guo

Wang

2007

MBoC

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“…Conversely, increases in cellular contractility have been shown to induce the simultaneous growth of both focal adhesions and the attached actin stress fibres [30]. Tension within the cell however, has been shown to be mediated by the clustering of the heterodimeric, transmembrane family of proteins known as integrins [23,31]. Activation of integrins is modulated by an allosteric conformational switch that accompanies the binding of the extracellular domain of the integrin receptor to its ligand [5,23].…”

Section: A) D) C) B) E)mentioning

confidence: 99%

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

Baron

et al. 2012

Oncogene

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“…10 Interestingly, nonmigratory cells exposed to the growth factors present in tissue culture medium appear to undergo continuous rearrangement of focal adhesions, despite remaining in place. 52 Since the receptors for these growth factors have been shown to physically associate with integrins, 53,54 it is tempting to speculate that integrins may function as 'coreceptors' for these growth factors. Ironically then, these growth factor receptors, which have been suggested to function via 'classic' on/off signaling mechanisms, are actually integrin-dependent.…”

Section: General Signaling Events Initiated By Integrinsmentioning

confidence: 99%

Integrins as a distinct subtype of dependence receptors

Stupack

2005

Cell Death Differ

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In the absence of their cognate ligand, dependence receptors trigger programmed cell death. This function is the defining feature of dependence receptors, which include members of several different protein families. The integrins are a family of heterodimeric receptors for extracellular matrix (ECM) proteins, mediating cell anchorage and migration. Integrins share characteristics with dependence receptors, and integrin binding to substrate ECM ligands is essential for cell survival. Although integrins do not conform in all characteristics to the established definitions of dependence receptors, alterations in the expression of integrins and their ligands during physiological and pathological events, such as wound healing, angiogenesis and tumorigenesis, do regulate cell fate in a ligand-dependent manner. This biosensory function of integrins fits well with our current concept of dependence receptor action, and thus integrins may rightly be considered to comprise a distinct subclass of dependence receptor.

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Focal Adhesion Motility Revealed in Stationary Fibroblasts

Cited by 319 publications

References 16 publications

Retrograde Fluxes of Focal Adhesion Proteins in Response to Cell Migration and Mechanical Signals

Retrograde Fluxes of Focal Adhesion Proteins in Response to Cell Migration and Mechanical Signals

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

Integrins as a distinct subtype of dependence receptors

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