Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1

Gough, Rosemarie E.; Jones, Max; Zacharchenko, Thomas; Le, Shimin; Yu, Miao; Jacquemet, Guillaume; Muench, Ste P.; Yan, Jie; Humphries, Jonathan D.; Jørgensen, Claus; Goult, Benjamin T.

doi:10.1016/j.jbc.2021.100837

Cited by 40 publications

(44 citation statements)

References 72 publications

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“…S2, I and J). In contrast, multiple structures of talin1 R7R8 solved alone (Gingras et al, 2010) and in complex (Chang et al, 2014;Zacharchenko et al, 2016;Gough et al, 2021) show no equivalent interactions between R7 and R8. Thus, it is possible that this more compact conformation might represent an autoinhibited conformation of TLNRD1, rendering some binding sites cryptic.…”

Section: Discussionmentioning

confidence: 76%

“…Talin R7R8 also binds to multiple other ligands, many of which contain leucine-aspartate motifs (LD motifs; Alam et al, 2014). R8 binds (i) Rap1-GTP-interacting adaptor molecule (RIAM), implicated in recruitment of talin to the leading edge of cells (Chang et al, 2014;Goult et al, 2013) and to filopodial protrusions (Lagarrigue et al, 2015); (ii) deleted in liver cancer 1 (DLC1; Zacharchenko et al, 2016;Li et al, 2011); (iii) paxillin (Zacharchenko et al, 2016); and (iv) cyclindependent kinase 1 (CDK1; Gough et al, 2021). R8 also contains a binding site for vinculin (Gingras et al, 2010) and the intermediate filament protein α-synemin (Sun et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Talin rod domain–containing protein 1 (TLNRD1) is a novel actin-bundling protein which promotes filopodia formation

Cowell

Jacquemet

Singh

et al. 2021

Journal of Cell Biology

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Talin is a mechanosensitive adapter protein that couples integrins to the cytoskeleton. Talin rod domain–containing protein 1 (TLNRD1) shares 22% homology with the talin R7R8 rod domains, and is highly conserved throughout vertebrate evolution, although little is known about its function. Here we show that TLNRD1 is an α-helical protein structurally homologous to talin R7R8. Like talin R7R8, TLNRD1 binds F-actin, but because it forms a novel antiparallel dimer, it also bundles F-actin. In addition, it binds the same LD motif–containing proteins, RIAM and KANK, as talin R7R8. In cells, TLNRD1 localizes to actin bundles as well as to filopodia. Increasing TLNRD1 expression enhances filopodia formation and cell migration on 2D substrates, while TLNRD1 down-regulation has the opposite effect. Together, our results suggest that TLNRD1 has retained the diverse interactions of talin R7R8, but has developed distinct functionality as an actin-bundling protein that promotes filopodia assembly.

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Section: Discussionmentioning

confidence: 76%

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. 2021

Journal of Cell Biology

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“…Folded (0) rod binders Many of these ligands contain LD motifs, helices with a leucine aspartate motif, that bind to the talin helix bundles via a helix addition mechanism. LD-containing proteins that bind talin in this way include RIAM (Goult et al, 2013b), KANK family proteins (Bouchet et al, 2016), CDK1 (Gough et al, 2021), DLC1, paxillin (Zacharchenko et al, 2016) and tensin (Atherton et al, 2021 preprint). LD-independent folded rod binders include F-actin (Hemmings et al, 1996), synemin (Sun et al, 2008), moesin (Beaty et al, 2014) and the talin F3 domain that mediates autoinhibition (Goksoy et al, 2008;Goult et al, 2009).…”

Section: The Talin Head Domainmentioning

confidence: 99%

“…b,c) (see poster). For example, phosphorylation of talin can alter the mechanical stability of the phosphorylated domain (Gough et al, 2021), altering the order in which the domains unfold and, by extension, the molecules recruited under equivalent tension conditions.…”

Section: Interdependence Of Talin and Integrinsmentioning

confidence: 99%

Talin in mechanotransduction and mechanomemory at a glance

Goult

Brown

Schwartz

2021

Journal of Cell Science

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Talins are cytoskeletal linker proteins that consist of an N-terminal head domain, a flexible neck region and a C-terminal rod domain made of 13 helical bundles. The head domain binds integrin β-subunit cytoplasmic tails, which triggers integrin conformational activation to increase affinity for extracellular matrix proteins. The rod domain links to actin filaments inside the cell to transmit mechanical loads and serves as a mechanosensitive signalling hub for the recruitment of many other proteins. The α-helical bundles function as force-dependent switches – proteins that interact with folded bundles are displaced when force induces unfolding, exposing previously cryptic binding sites for other ligands. This leads to the notion of a talin code. In this Cell Science at a Glance article and the accompanying poster, we propose that the multiple switches within the talin rod function to process and store time- and force-dependent mechanical and chemical information.

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“…In addition, integrins and the ECM are known to contribute to the hallmarks of cancer [31,32]. There is also growing evidence for a mechanistic coupling of integrin function with the cell cycle to govern cell proliferation [33][34][35], and inhibition of the IAC component focal adhesion kinase limits tumour progression in the KPC mouse model of human PDAC [36]. Integrins and IACs are therefore considered important regulators of the pathological development of cancer and provide opportunities for therapeutic intervention [7,8,31,37,38].…”

Section: Introductionmentioning

confidence: 99%

Pancreatic ductal adenocarcinoma cells employ integrin α6β4 to form hemidesmosomes and regulate cell proliferation

Humphries

Zha

Burns

et al. 2021

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis due to its aggressive progression, late detection and lack of druggable driver mutations, which often combine to result in unsuitability for surgical intervention. Together with activating mutations of the small GTPase KRas, which are found in over 90% of PDAC tumours, a contributory factor for PDAC tumour progression is formation of a rigid extracellular matrix (ECM) and associated desmoplasia. This response leads to aberrant integrin signalling, and accelerated proliferation and invasion. To identify the integrin adhesion systems that operate in PDAC, we analysed a range of pancreatic ductal epithelial cell models using 2D, 3D and organoid culture systems. Proteomic analysis of isolated integrin receptor complexes from human pancreatic ductal epithelial (HPDE) cells predominantly identified integrin α6β4 and hemidesmosome components, rather than classical focal adhesion components. Electron microscopy, together with immunofluorescence, confirmed the formation of hemidesmosomes by HPDE cells, both in 2D and 3D culture systems. Similar results were obtained for the human PDAC cell line, SUIT-2. Analysis of HPDE cell secreted proteins and cell-derived matrices (CDM) demonstrated that HPDE cells secrete a range of laminin subunits and form a hemidesmosome-specific, laminin 332-enriched ECM. Expression of mutant KRas (G12V) did not affect hemidesmosome composition or formation by HPDE cells. Cell-ECM contacts formed by mouse and human PDAC organoids were also assessed by electron microscopy. Organoids generated from both the PDAC KPC mouse model and human patient-derived PDAC tissue displayed features of acinar-ductal cell polarity, and hemidesmosomes were visible proximal to prominent basement membranes. Furthermore, electron microscopy identified hemidesmosomes in normal human pancreas. Depletion of integrin β4 using siRNA reduced cell proliferation in both SUIT-2 and HPDE cells, reduced the number of SUIT-2 cells in S-phase, and induced G1 cell cycle arrest, indicating a requirement for α6β4-mediated adhesion for cell cycle progression and growth. Taken together, these data suggest that laminin-binding adhesion mechanisms in general, and hemidesmosome-mediated adhesion in particular, may be under-appreciated in the context of PDAC.

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Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1

Cited by 40 publications

References 72 publications

Talin rod domain–containing protein 1 (TLNRD1) is a novel actin-bundling protein which promotes filopodia formation

Talin rod domain–containing protein 1 (TLNRD1) is a novel actin-bundling protein which promotes filopodia formation

Talin in mechanotransduction and mechanomemory at a glance

Pancreatic ductal adenocarcinoma cells employ integrin α6β4 to form hemidesmosomes and regulate cell proliferation

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