Vinculin controls talin engagement with the actomyosin machinery

Atherton, Paul; Stutchbury, Benjamin; Wang, De Yao; Jethwa, Devina; Tsang, Ricky; Meiler-Rodriguez, Eugenia; Wang, Pengbo; Bate, Neil; Zent, Roy; Barsukov, Igor; Goult, Benjamin T.; Critchley, David R.; Ballestrem, Christoph

doi:10.1038/ncomms10038

Cited by 191 publications

(309 citation statements)

References 65 publications

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“…This triggers vinculin interactions and leads to adhesion maturation 23. In contrast, ABS2, in the centre of the rod provides the tension‐bearing actin connection 84, 85. As with the integrin connections, the actin‐binding sites in talin2 bind more tightly to actin than the equivalent regions in talin1 (35 and our unpublished data).…”

Section: Talin1 and Talin2 Rod Interactionsmentioning

confidence: 86%

“…As talin domains unfold, starting with R3, the initial mechanosensor in talin 21, 23, 24, vinculin‐binding sites are exposed and talin:vinculin interactions can now occur. R3 unfolding also reveals the high affinity actin‐binding site in talin, ABS 2 that can then activate tension‐bearing actin connections 84, 85. As domains unfold, the binding sites for ligands that engage the folded rod domains are destroyed, as is the case for RIAM binding to R3.…”

Section: Talin1 and Talin2 Rod Interactionsmentioning

confidence: 99%

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

Gough

Goult

2018

FEBS Letters

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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.

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Section: Talin1 and Talin2 Rod Interactionsmentioning

confidence: 86%

Section: Talin1 and Talin2 Rod Interactionsmentioning

confidence: 99%

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

Gough

Goult

2018

FEBS Letters

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“…Cells expressing talin with mutations in the ABS3 domain that compromise actin binding do not develop functional FAs, and the mutant talin is not associated with actin filaments. However, co-expression of a constitutively active T12 vinculin mutant (D974A,K975A,R976A,R978A) (45) fully rescued FA formation (46). Inclusion of the vinculin A50I mutation, which inhibits vinculin-talin binding, prevented this rescue.…”

Section: Possible Roles Of Pip 2 Binding In Vinculin Recruitment and mentioning

confidence: 99%

Mechanisms and Functions of Vinculin Interactions with Phospholipids at Cell Adhesion Sites

Izard

Brown

2016

Journal of Biological Chemistry

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The cytoskeletal protein vinculin is a major regulator of cell adhesion and attaches to the cell surface by binding to specific phospholipids. Structural, biochemical, and biological studies provided much insight into how vinculin binds to membranes, what components it recognizes, and how lipid binding is regulated. Here we discuss the roles and mechanisms of phospholipids in regulating the structure and function of vinculin and of its muscle-specific metavinculin splice variant. A full appreciation of these processes is necessary for understanding how vinculin regulates cell motility, migration, and wound healing, and for understanding of its role in cancer and cardiovascular diseases.Inositol phospholipids are crucial regulators of cell physiology, and their head group interactions play fundamental roles in controlling membrane/cytosol interfaces. In addition to signal transduction at the cell surface, these lipids regulate a range of cellular processes including membrane trafficking, polarity, nuclear events, the permeability and transport functions of membranes, and cytoskeletal organization. Phosphoinositides are spatially and temporally regulated at sites of actin assembly andcytoskeletonremodeling.Phosphatidylinositol4,5-bisphosphate (PIP 2 ) 2 is a precursor of the second messengers diacylglycerol, inositol 3,4,5-trisphosphate, and phosphatidyl 3,4,5-trisphosphate and is crucial in the organization of the actin cytoskeleton at the plasma membrane (1). PIP 2 participates in the recruitment and activation of a wide variety of adaptor proteins and actin regulatory proteins. During the assembly of focal adhesions (FAs), the cytoskeletal protein talin recruits an isoform of phosphatidylinositol 4-phosphate 5-kinase (PIP 5 K␥90) that catalyzes the phosphorylation of phosphatidyl 4-phosphate to generate a local enrichment of PIP 2 (2-4). This localized pool of PIP 2 is critical for the subsequent recruitment of FA proteins and maturation of the FAs (5, 6). Vinculin is an early and essential component of nascent cell-matrix adhesion and acts as a scaffold by binding to several actin-organizing proteins. In mature FAs, vinculin is a key component of the "molecular clutch" that mediates the transmission of force from cytoplasmic F-actin to membrane-bound integrins (7-9). Cytosolic vinculin mainly adopts a closed conformation that is kept inactive through extensive hydrophobic interactions of its globular 91-kDa head (VH, residues 1-840) that harbors binding sites for talin, ␣-actinin, or ␣-catenin to VH (10 -13) and its 21-kDa tail (Vt, residues 879 -1066) domains (14, 15), which are connected via a proline-rich linker (Fig. 1, A and B). The intramolecular VH-Vt interaction masks the binding sites of F-actin (16, 17), PIP 2 (18), and raver1 (19,20) to Vt. Cytoplasmic vinculin must be recruited to FAs and activated to expose ligandbinding sites through a complex process that is not completely understood (21).Vinculin is essential during development due to its role in regulating adhesion and motility, as well as cel...

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“…To investigate whether LIPUS stimulation directly affects the dynamics of vinculin within the FA, we used fluorescence loss after photoactivation (FLAP) (Atherton et al, 2015) to investigate the turnover of photoactivatable GFP (PAGFP)-vinculin before and during LIPUS stimulation. For these experiments, we used NIH3T3 fibroblasts.…”

Section: Sensing Of Lipus Is Mediated Through Vinculin and Its Link Tmentioning

confidence: 99%

Low-intensity pulsed ultrasound promotes cell motility through vinculin-controlled Rac1 GTPase activity

Atherton

Lausecker

Harrison³

et al. 2017

Journal of Cell Science

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Low-intensity pulsed ultrasound (LIPUS) is a therapy used clinically to promote healing. Using live-cell imaging we show that LIPUS stimulation, acting through integrin-mediated cell-matrix adhesions, rapidly induces Rac1 activation associated with dramatic actin cytoskeleton rearrangements. Our study demonstrates that the mechanosensitive focal adhesion (FA) protein vinculin, and both focal adhesion kinase (FAK, also known as PTK2) and Rab5 (both the Rab5a and Rab5b isoforms) have key roles in regulating these effects. Inhibiting the link of vinculin to the actin-cytoskeleton abolished LIPUS sensing. We show that this vinculin-mediated link was not only critical for Rac1 induction and actin rearrangements, but was also important for the induction of a Rab5-dependent increase in the number of early endosomes. Expression of dominant-negative Rab5, or inhibition of endocytosis with dynasore, also blocked LIPUSinduced Rac1 signalling events. Taken together, our data show that LIPUS is sensed by cell matrix adhesions through vinculin, which in turn modulates a Rab5-Rac1 pathway to control ultrasound-mediated endocytosis and cell motility. Finally, we demonstrate that a similar FAK-Rab5-Rac1 pathway acts to control cell spreading upon fibronectin.

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Vinculin controls talin engagement with the actomyosin machinery

Cited by 191 publications

References 65 publications

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

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

Mechanisms and Functions of Vinculin Interactions with Phospholipids at Cell Adhesion Sites

Low-intensity pulsed ultrasound promotes cell motility through vinculin-controlled Rac1 GTPase activity

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