β1- and αv-class integrins cooperate to regulate myosin II during rigidity sensing of fibronectin-based microenvironments

Schiller, Herbert B.; Hermann, Michaela-Rosemarie; Polleux, Julien; Vignaud, Timothée; Zanivan, Sara; Friedel, Caroline C.; Sun, Zhiqi; Raducanu, Aurelia; Gottschalk, Kay‐E.; Théry, Manuel; Mann, Matthias; Fässler, Reinhard

doi:10.1038/ncb2747

Cited by 392 publications

(475 citation statements)

References 60 publications

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“…It is therefore likely that biochemical signals derived from endothelial adhesion to laminin 511 act downstream to regulate actin arrangements and thereby cortical stiffness and mechanotransduction processes (Hutcheson & Griffith, 1996; Tzima et al , 2001). Candidate downstream signalling molecules include RhoA, which has been implicated in force generation via β1‐integrins (Schiller et al , 2013) and shear responses (Jalali et al , 1998; Tzima et al , 2001), and Src kinase (Huveneers & Danen, 2009; Martinez‐Rico et al , 2010). …”

Section: Discussionmentioning

confidence: 99%

Endothelial basement membrane laminin 511 is essential for shear stress response

Russo¹,

Luik²,

Yousif³

et al. 2016

The EMBO Journal

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Shear detection and mechanotransduction by arterial endothelium requires junctional complexes containing PECAM‐1 and VE‐cadherin, as well as firm anchorage to the underlying basement membrane. While considerable information is available for junctional complexes in these processes, gained largely from in vitro studies, little is known about the contribution of the endothelial basement membrane. Using resistance artery explants, we show that the integral endothelial basement membrane component, laminin 511 (laminin α5), is central to shear detection and mechanotransduction and its elimination at this site results in ablation of dilation in response to increased shear stress. Loss of endothelial laminin 511 correlates with reduced cortical stiffness of arterial endothelium in vivo, smaller integrin β1‐positive/vinculin‐positive focal adhesions, and reduced junctional association of actin–myosin II. In vitro assays reveal that β1 integrin‐mediated interaction with laminin 511 results in high strengths of adhesion, which promotes p120 catenin association with VE‐cadherin, stabilizing it at cell junctions and increasing cell–cell adhesion strength. This highlights the importance of endothelial laminin 511 in shear response in the physiologically relevant context of resistance arteries.

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Section: Discussionmentioning

confidence: 99%

Endothelial basement membrane laminin 511 is essential for shear stress response

Russo¹,

Luik²,

Yousif³

et al. 2016

The EMBO Journal

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“…PEA-15 is a multifunctional protein known (1) to modulate α5β1 integrin activity, 38 (2) to be included in the α5β1 adhesome 39 and (3) to bind to Fas-associated protein with death domain (FADD) and/or Casp 8 in the apoptotic death-inducing signaling complex. 32 PEA-15 can be phosphorylated on ser116 by AKT and on ser104 by protein kinase C leading to different functional implications.…”

Section: Discussionmentioning

confidence: 99%

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

et al. 2015

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Integrin α5β1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5β1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy. However, p53-dependent apoptosis is not always achieved by p53-reactivating compounds such as Nutlin-3a, although full transcriptional activity of p53 could be obtained. Here we investigated whether integrin α5β1 functional inhibition or repression could sensitize glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α5β1 integrin-specific blocking antibodies or small RGD-like antagonists in association with Nutlin-3a triggered a caspase (Casp) 8/Casp 3-dependent strong apoptosis in glioma cells expressing a functional p53. We deciphered the molecular mechanisms involved and we showed the crucial role of two anti-apoptotic proteins, phosphoprotein enriched in astrocytes 15 (PEA-15) and survivin in glioma cell apoptotic outcome. PEA-15 is under α5β1 integrin/AKT (protein kinase B) control and survivin is a p53-repressed target. Moreover, interconnections between integrin and p53 pathways were revealed. Indeed PEA-15 repression by specific small-interfering RNA (siRNA)-activated p53 pathway to repress survivin and conversely survivin repression by specific siRNA decreased α5β1 integrin expression. This pro-apoptotic loop could be generalized to several glioma cell lines, whatever their p53 status, inasmuch PEA-15 and survivin protein levels were decreased. Our findings identify a novel mechanism whereby inhibition of α5β1 integrin and activation of p53 modulates two anti-apoptotic proteins crucially involved in the apoptotic answer of glioma cells. Importantly, our results suggest that high-grade glioma expressing high level of α5β1 integrin may benefit from associated therapies including integrin antagonists and repressors of survivin expression.

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“…Key questions relating to the control of integrin activity include how is the intracellular location of distinct adhesion complexes regulated and (2) how do cells utilise different integrin receptors, which bind the same substrate, to elicit distinct cellular responses. Our understanding of the latter was recently advanced in a comprehensive comparison of the specific functions of αv-and β1-integrins, in response to binding fibronection (Schiller et al 2013). In addition to the culture models used to study integrins, it is imperative that we also determine how tissue-specific functions of integrins are regulated in vivo.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Structural and mechanical functions of integrins

2013

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Integrins are ubiquitously expressed cell surface receptors that play a critical role in regulating the interaction between a cell and its microenvironment to control cell fate. These molecules are regulated either via their expression on the cell surface or through a unique bidirectional signalling mechanism. However, integrins are just the tip of the adhesome iceberg, initiating the assembly of a large range of adaptor and signalling proteins that mediate the structural and signalling functions of integrin. In this review, we summarise the structure of integrins and mechanisms by which integrin activation is controlled. The different adhesion structures formed by integrins are discussed, as well as the mechanical and structural roles integrins play during cell migration. As the function of integrin signalling can be quite varied based on cell type and context, an in depth understanding of these processes will aid our understanding of aberrant adhesion and migration, which is often associated with human pathologies such as cancer.

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β1- and αv-class integrins cooperate to regulate myosin II during rigidity sensing of fibronectin-based microenvironments

Cited by 392 publications

References 60 publications

Endothelial basement membrane laminin 511 is essential for shear stress response

Endothelial basement membrane laminin 511 is essential for shear stress response

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

Structural and mechanical functions of integrins

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