Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force

Vigouroux, Clémence; Henriot, Véronique; Clainche, Christophe Le

doi:10.1038/s41467-020-16922-1

Cited by 33 publications

(29 citation statements)

References 54 publications

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“…Second, IVVI mutant in talin R3 has been reported to prevent mechanotransduction, as assessed by traction exertion and YAP nuclear localization ( Elosegui-Artola et al, 2016 ). Additionally, based on published data ( Goult et al, 2013 ; Lee et al, 2013 ), the R3 domain is likely to be bound to the Rap1-interacting adaptor molecule (RIAM) prior to the force ( Vigouroux et al, 2020 ). Thus, early, tension-independent interactions between talin and vinculin is more likely mediated by a different site, for which our data suggests the talin R8 domain.…”

Section: Discussionmentioning

confidence: 99%

Pre-complexation of talin and vinculin without tension is required for efficient nascent adhesion maturation

Han

Azarova

Whitewood

et al. 2021

eLife

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Talin and vinculin are mechanosensitive proteins that are recruited early to integrin-based nascent adhesions (NAs). In two epithelial cell systems with well-delineated NA formation, we find these molecules concurrently recruited to the subclass of NAs maturing to focal adhesions. After the initial recruitment under minimal load, vinculin accumulates in maturing NAs at a ~ fivefold higher rate than in non-maturing NAs, and is accompanied by a faster traction force increase. We identify the R8 domain in talin, which exposes a vinculin-binding-site (VBS) in the absence of load, as required for NA maturation. Disruption of R8 domain function reduces load-free vinculin binding to talin, and reduces the rate of additional vinculin recruitment. Taken together, these data show that the concurrent recruitment of talin and vinculin prior to mechanical engagement with integrins is essential for the traction-mediated unfolding of talin, exposure of additional VBSs, further recruitment of vinculin, and ultimately, NA maturation.

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Section: Discussionmentioning

confidence: 99%

Pre-complexation of talin and vinculin without tension is required for efficient nascent adhesion maturation

Han

Azarova

Whitewood

et al. 2021

eLife

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“…Talin is the main scaffold protein in focal adhesions which form at the leading edge of a polarised cell. Talin links the intracellular tails of integrins to the actin cytoskeleton and mechanical forces exerted on talin can disrupt and reveal binding sites leading to formation of mature multiprotein FA complexes [16][17][18] . These are dynamic processes regulated by a complex signalling network, gathering information from intracellular and extracellular events.…”

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confidence: 99%

Cancer associated talin point mutations disorganise cell adhesion and migration

Azizi

Cowell

Mykuliak

et al. 2021

Sci Rep

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Talin-1 is a key component of the multiprotein adhesion complexes which mediate cell migration, adhesion and integrin signalling and has been linked to cancer in several studies. We analysed talin-1 mutations reported in the Catalogue of Somatic Mutations in Cancer database and developed a bioinformatics pipeline to predict the severity of each mutation. These predictions were then assessed using biochemistry and cell biology experiments. With this approach we were able to identify several talin-1 mutations affecting integrin activity, actin recruitment and Deleted in Liver Cancer 1 localization. We explored potential changes in talin-1 signalling responses by assessing impact on migration, invasion and proliferation. Altogether, this study describes a pipeline approach of experiments for crude characterization of talin-1 mutants in order to evaluate their functional effects and potential pathogenicity. Our findings suggest that cancer related point mutations in talin-1 can affect cell behaviour and so may contribute to cancer progression.

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“…Second, it has been reported that IVVI mutant in talin R3 prevents mechanotransduction, as assessed by traction exertion and YAP nuclear localization 55 . Additionally, based on published data 30,67 , the R3 domain is likely to be bound to the Rap1-interacting adaptor molecule (RIAM) prior to the force 68 . Thus, early, tension-independent interactions between talin and vinculin is more likely to mediated by a different site, for which our data suggests the talin R8 domain.…”

mentioning

confidence: 99%

Talin-vinculin precomplex drives adhesion maturation by accelerated force transmission and vinculin recruitment

Han

Azarova

Whitewood

et al. 2019

Preprint

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Talin, vinculin, and paxillin are mechanosensitive proteins that are recruited early to nascent integrin-based adhesions (NAs). Using machine learning, high-resolution traction force microscopy, single-particle-tracking and fluorescence fluctuation time-series analysis, we find that, only in the NAs that eventually mature to focal adhesions, all three molecules are recruited concurrently and in synchrony with force onset. Thereafter, vinculin assembles at ~5 fold higher rates than in non-maturing NAs. We identify a domain in talin, R8, which exposes a vinculinbinding-site (VBS) without requiring tension. Stabilizing this domain via mutation lowers tensionfree vinculin binding in conjunction with talin, impairs maturation of NAs, and reduces the rate of additional vinculin recruitment after force onset. Taken together, our data show that talin forms a complex with vinculin, before association with integrins, which is essential for NA maturation by talin's effective unfolding and exposure of additional VBSs that induce fast force growth and further vinculin binding. Cell-matrix adhesions are multi-molecular complexes that link the extracellular matrix (ECM), typically via integrin transmembrane receptors, to the actin cytoskeleton. Being both a forcetransmitter and a force-sensor, cell-matrix adhesions are critical to cell morphogenesis and mechanosensation (Discher et al., 2005;Parsons et al., 2010). Indeed, in response to ECM changes, adhesions undergo constant changes in morphology and motion that involve recruitment and recycling of a large number of adhesion molecules. For example, nascent adhesions (NAs) emerge within the actin-dense cell lamellipodia and then slide in the direction opposite to the protrusion as a result of polymerization-driven flow of the actin network (Parsons et al., 2010). Many of these NAs, which are less than 0.5 µm long, and thus in a light microscope only resolved as diffraction-limited spots, turn over early; but some of them mature into longer focal complexes (FCs, >0.5 µm in length) and focal adhesions (FAs, >2 µm in length) at the lamellipodia-lamella interface (Gardel et al., 2010;Parsons et al., 2010). During this progression, NAs go through multiple decision processes regarding fate and morphology. Compared to the well-studied FAs, for which the interconnection between structure, signaling, and force transmission is largely understood (Balaban et al.

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Talin dissociates from RIAM and associates to vinculin sequentially in response to the actomyosin force

Cited by 33 publications

References 54 publications

Pre-complexation of talin and vinculin without tension is required for efficient nascent adhesion maturation

Pre-complexation of talin and vinculin without tension is required for efficient nascent adhesion maturation

Cancer associated talin point mutations disorganise cell adhesion and migration

Talin-vinculin precomplex drives adhesion maturation by accelerated force transmission and vinculin recruitment

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