Disruption of thetalin gene arrests mouse development at the gastrulation stage

Monkley, Susan J.; Zhou, Xin; Kinston, Sarah; Giblett, Susan; Hemmings, Lance; Priddle, Helen; Brown, Jane; Pritchard, Catrin; Critchley, David R.; Fässler, Reinhard

doi:10.1002/1097-0177(2000)9999:9999<::aid-dvdy1079>3.0.co;2-y

Cited by 200 publications

(133 citation statements)

References 53 publications

(50 reference statements)

Supporting

Mentioning

123

Contrasting

Unclassified

Order By: Relevance

“…Two highly homologous talin genes, talin1 (tln1) and talin2 (tln2), have been identified; loss of talin1 is embryonic-lethal, whereas talin2-null mice are viable and fertile (22,23). Nevertheless, both isoforms are expressed in most cell types (24) (Fig.…”

Section: Resultsmentioning

confidence: 66%

Talin determines the nanoscale architecture of focal adhesions

Liu

Wang

Goh

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

165

169

View full text Add to dashboard Cite

Insight into how molecular machines perform their biological functions depends on knowledge of the spatial organization of the components, their connectivity, geometry, and organizational hierarchy. However, these parameters are difficult to determine in multicomponent assemblies such as integrin-based focal adhesions (FAs). We have previously applied 3D superresolution fluorescence microscopy to probe the spatial organization of major FA components, observing a nanoscale stratification of proteins between integrins and the actin cytoskeleton. Here we combine superresolution imaging techniques with a protein engineering approach to investigate how such nanoscale architecture arises. We demonstrate that talin plays a key structural role in regulating the nanoscale architecture of FAs, akin to a molecular ruler. Talin diagonally spans the FA core, with its N terminus at the membrane and C terminus demarcating the FA/stress fiber interface. In contrast, vinculin is found to be dispensable for specification of FA nanoscale architecture. Recombinant analogs of talin with modified lengths recapitulated its polarized orientation but altered the FA/stress fiber interface in a linear manner, consistent with its modular structure, and implicating the integrin-talin-actin complex as the primary mechanical linkage in FAs. Talin was found to be ∼97 nm in length and oriented at ∼15°relative to the plasma membrane. Our results identify talin as the primary determinant of FA nanoscale organization and suggest how multiple cellular forces may be integrated at adhesion sites.superresolution microscopy | focal adhesions | talin | mechanobiology | nanoscale architecture C ell adhesion to the ECM is a highly coordinated process that involves ECM-specific recognition by integrin transmembrane receptors, and their aggregation with numerous cytoplasmic proteins into dense supramolecular complexes called focal adhesions (FAs) (1). Actin stress fibers terminate at FAs where actomyosin contractility is transmitted to the ECM, generating traction (2-5). Mechanical tension impinging on each FA is implicated in key steps including the elongation, reinforcement, and maintenance of the FA structures (6). FA mechanotransduction is a major aspect of cellular microenvironment sensing with wide-ranging consequences in physiological and pathological processes (7-10). However, molecular-scale spatial parameters that specify FA nanoscale organization have been difficult to access experimentally. Nevertheless, these are essential to understand how mechanosensitivity arises within such complex molecular machines (11-15).Previously 3D superresolution fluorescence microscopy has unveiled the nanoscale organization of major FA components, whereby a core region of ∼30 nm interposes between the integrin and the actin cytoskeleton along the vertical (z) axis (16). The FA core consists of a membrane-proximal layer that contains signaling proteins such as FAK (focal adhesion kinase) and paxillin, an intermediate zone that contains force-transduction proteins s...

show abstract

Section: Resultsmentioning

confidence: 66%

Talin determines the nanoscale architecture of focal adhesions

Liu

Wang

Goh

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

165

169

View full text Add to dashboard Cite

show abstract

“…Talin1 knockout is also embryonic lethal in mice due to arrested gastrulation, indicating a key role in early development 4. In contrast talin2, which was only discovered following publication of the human genome sequence 8, 9 has received less attention, and the fact that talin2 knockout mice are viable and fertile 10 suggests isoform redundancy.…”

Section: Integrin Adhesions: Linking the Cell To The Extracellular Mamentioning

confidence: 99%

The tale of two talins – two isoforms to fine‐tune integrin signalling

Gough

Goult

2018

FEBS Letters

View full text Add to dashboard Cite

Talins are cytoplasmic adapter proteins essential for integrin‐mediated cell adhesion to the extracellular matrix. Talins control the activation state of integrins, link integrins to cytoskeletal actin, recruit numerous signalling molecules that mediate integrin signalling and coordinate recruitment of microtubules to adhesion sites via interaction with KANK (kidney ankyrin repeat‐containing) proteins. Vertebrates have two talin genes, TLN1 and TLN2. Although talin1 and talin2 share 76% protein sequence identity (88% similarity), they are not functionally redundant, and the differences between the two isoforms are not fully understood. In this Review, we focus on the similarities and differences between the two talins in terms of structure, biochemistry and function, which hint at subtle differences in fine‐tuning adhesion signalling.

show abstract

“…Its binding to the membrane-distal section of the β-tail is a common and necessary event in integrin activation in many cell types and events including T-cell adhesion and migration on ICAM-1 111 , lymphocyte-endothelial cell interactions 112 , macrophage-mediated phagocytosis by α M β 2 integrin 113 , α IIb β 3 -mediated platelet adhesion and spreading 110 and clathrin-mediated endocytosis in the neuronal synapse 114 . Whole-animal disruption of talin expression is lethal in embryonic mice 115 but conditional inhibition of talin expression demonstrates that talin is required specifically for the outside-in activation of integrins in vivo 116 .…”

Section: Role Of Integrin Cytoplasmic Tailsmentioning

confidence: 99%