Cancer associated talin point mutations disorganise cell adhesion and migration

Azizi, Latifeh; Cowell, Alana R.; Mykuliak, Vasyl V.; Goult, Benjamin T.; Turkki, Paula; Hytönen, Vesa P.

doi:10.1101/2020.03.25.008193

Cited by 4 publications

(3 citation statements)

References 78 publications

(105 reference statements)

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“…To distinguish among these possibilities, we first more closely examined the dimerization of ABS3, which had been reported to form a constitutive dimer (Azizi et al, 2020). In our hands, ABS3 dimerization is a dynamic equilibrium at micromolar concentrations, as determined by native PAGE (Fig.…”

mentioning

confidence: 99%

The C-terminal actin binding domain of talin forms an asymmetric catch bond with F-actin

Owen

Bax

Weis

et al. 2020

Preprint

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Focal adhesions (FAs) are large, integrin-based adhesion complexes that link cells to the extracellular matrix (ECM). Previous work demonstrates that FAs form only when and where they are necessary to transmit force between the cellular cytoskeleton and the ECM, but how this occurs remains poorly understood. Talin is a 270 kDa adapter protein that links integrins to filamentous (F)-actin and recruits additional components during FA assembly in a force-dependent manner. Cell biological and developmental data demonstrate that the third, and C-terminal, F-actin binding site (ABS3) of talin is required for normal FA formation. However, ABS3 binds F-actin only weakly in in vitro, biochemical assays. We used a single-molecule optical trap assay to examine how and whether ABS3 binds F-actin under physiologically relevant, pN mechanical loads. We find that ABS3 forms a directional catch bond with F-actin when force is applied towards the pointed end of the actin filament, with binding lifetimes more than 100-fold longer than when force is applied towards the barbed end. Long-lived bonds to F-actin under load require the ABS3 C-terminal dimerization domain, whose cleavage is known to regulate focal adhesion turnover. Our results support a mechanism in which talin ABS3 preferentially binds and orients actin filaments with barbed ends facing the cell periphery, thus nucleating long-range order in the actin cytoskeleton. We suggest that talin ABS3 may function as a molecular AND gate that allows FA growth only when sufficient integrin density, F-actin polarization, and mechanical tension are simultaneously present.

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confidence: 99%

The C-terminal actin binding domain of talin forms an asymmetric catch bond with F-actin

Owen

Bax

Weis

et al. 2020

Preprint

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“…The Talin family consists of two members, Talin1 and Talin2, which are expressed nearly in all tissues and mainly in the heart, brain and muscles, respectively [30]. Research into the biological function of Talin1 has been ongoing and its structural function of activating integrin and facilitating the clustering and assembling of focal adhesion has been well-established [31].…”

Section: Discussionmentioning

confidence: 99%

Talin1 promotes HCC progression by regulating NRG1/PI3K/AKT axis

Liu

Zheng

et al. 2023

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Hepatocellular carcinoma (HCC) is the world's third leading cause of cancer death, with metastasis being the predominant cause of treatment failure. We aim to explore the role of Talin1 in HCC and its underlying mechanism. We conducted bioinformatic analysis, qRT-PCR, Immunohistochemical staining, and western blot to detect the mRNA and protein expression levels of Talin1 in HCC tissues and adjacent samples from databases and our clinical center. Cell viability assays (CCK8 assay), transwell assays, and Xenograft tumor models were used to assess the effect of Talin1 on HCC cell proliferation, invasion, and migration both in vitro and in vivo. We also investigated the NRG1 protein, which is known to activate the PI3K/AKT pathway, to further elucidate the mechanism. Our results indicate that Talin1 is substantially more expressed in HCC tissues than in tumor-adjacent tissues in terms of both mRNA and protein levels. High expression levels of Talin1 were linked to poorer prognosis in HCC patients. Downregulation of Talin1 inhibited HCC cell proliferation and metastasis both in vitro and in vivo. Further, we found that Talin1 regulates NRG1, which activates the downstream PI3K/AKT pathway to facilitate HCC progression. Our findings suggest that Talin1 is an oncogene that regulates NRG1/ PI3K/AKT pathway to promote HCC progression. These findings provide new insight into HCC development and may offer novel treatment strategies for HCC.

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“…This complex protein interaction network suggests that R7R8 plays a key role in coordinating multiple processes including crosstalk between all three cytoskeletal networks. Mutations in talin R7R8, obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC), can perturb this coordination and increase invasion and migration in cells (Azizi et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Talin Rod Domain Containing Protein 1 (TLNRD1) is a novel actin-bundling protein which promotes filopodia formation

Cowell

Jacquemet

Singh

et al. 2020

Preprint

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Talin is a mechanosensitive adapter protein which couples integrins to the cytoskeleton and regulates integrin-mediated adhesion. Talin rod domain-containing protein-1 (TLNRD1) shares 22% homology with the R7R8 domains of talin, and is highly conserved throughout vertebrate evolution, however little is known about its function. Here we show that TLNRD1 is an α-helical protein which shares the same atypical topology as talin R7R8, but forms a novel antiparallel dimer arrangement. Actin co-sedimentation assays and electron microscopy reveal TLNRD1 is an actin-bundling protein that forms tight actin bundles. In addition, TLNRD1 binds to the same LD-motif containing proteins, RIAM and KANK, as talin, and thus may act in competition with talin. Filopodia are cell protrusions supported by tightly bundled actin filaments and TLNRD1 localises to filopodia tips, increases filopodia number and promotes cell migration in 2D. Together our results suggest that TLNRD1 has similar functionality to talin R7R8, serving as a nexus between the actin and microtubule cytoskeletons independent of adhesion complexes.

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Cancer associated talin point mutations disorganise cell adhesion and migration

Cited by 4 publications

References 78 publications

The C-terminal actin binding domain of talin forms an asymmetric catch bond with F-actin

The C-terminal actin binding domain of talin forms an asymmetric catch bond with F-actin

Talin1 promotes HCC progression by regulating NRG1/PI3K/AKT axis

Talin Rod Domain Containing Protein 1 (TLNRD1) is a novel actin-bundling protein which promotes filopodia formation

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