Integrins as therapeutic targets: lessons and opportunities

Cox, Dermot; Brennan, Marian; Moran, Niamh

doi:10.1038/nrd3266

Cited by 402 publications

(351 citation statements)

References 201 publications

(157 reference statements)

Supporting

Mentioning

345

Contrasting

Unclassified

Order By: Relevance

“…However, clinical trials have not shown the anticipated success. One reason for this observation could be the importance of integrins in other key physiological systems (6). A better understanding of the involved molecular signaling pathways and physiological regulation mechanisms may unravel opportunities to tackle leukocyte recruitment and inflammation more specifically and, ultimately, more successfully.…”

Section: Integrin Regulation During Leukocyte Recruitmentmentioning

confidence: 99%

Integrin Regulation during Leukocyte Recruitment

Herter

Zarbock

2013

The Journal of Immunology

166

135

View full text Add to dashboard Cite

Integrins are recognized as vital players in leukocyte recruitment. Integrin malfunction causes severe disease patterns characterized by the inability to fight pathogens. Although inflammatory reactions are beneficial and necessary for host defense, these reactions have to be controlled to prevent tissue destruction and harmful sequelae. In this review, we discuss the different signaling pathways leading to the change of integrin adhesiveness in neutrophils, monocytes, and lymphocytes. We thereby focus on the importance of integrin activation for the different steps of the leukocyte recruitment cascade, including rolling, adhesion, postadhesion strengthening, intravascular crawling, and transmigration, as each step necessitates the proper functioning of a distinct set of integrin molecules that has to be activated specifically. Additionally, we discuss endogenous mechanisms that balance and counteract integrin activation and limit leukocyte recruitment at the site of inflammation. Further insight into these complex mechanisms may provide new approaches for developing new anti-inflammatory therapies.

show abstract

Section: Integrin Regulation During Leukocyte Recruitmentmentioning

confidence: 99%

Integrin Regulation during Leukocyte Recruitment

Herter

Zarbock

2013

The Journal of Immunology

166

135

View full text Add to dashboard Cite

show abstract

“…However, how the membrane-targeting and integrin binding of talin-FERM are spatiotemporally regulated to control the dynamics of integrin adhesion is not understood. This issue is important, since uncontrolled talin activity may lead to dysfunction of integrins, which is linked to many human disorders, including thrombosis, stroke, bleeding, infections, and cancer metastasis [18]. Talin can adopt inactive and active states during dynamic cell adhesion events, but the underlying molecular basis for this transition is elusive [2].…”

Section: Introductionmentioning

confidence: 99%

A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion

et al. 2012

View full text Add to dashboard Cite

The activation of heterodimeric (α/β) integrin transmembrane receptors by cytosolic protein talin is crucial for regulating diverse cell-adhesion-dependent processes, including blood coagulation, tissue remodeling, and cancer metastasis. This process is triggered by the coincident binding of N-terminal FERM (four-point-one-protein/ezrin/radixin/moesin) domain of talin (talin-FERM) to the inner membrane surface and integrin β cytoplasmic tail, but how these binding events are spatiotemporally regulated remains obscure. Here we report the crystal structure of a dormant talin, revealing how a C-terminal talin rod segment (talin-RS) self-masks a key integrin-binding site on talin-FERM via a large interface. Unexpectedly, the structure also reveals a distinct negatively charged surface on talin-RS that electrostatically hinders the talin-FERM binding to the membrane. Such a dual inhibitory topology for talin is consistent with the biochemical and functional data, but differs significantly from a previous model. We show that upon enrichment with phosphotidylinositol-4,5-bisphosphate (PIP2) -a known talin activator, membrane strongly attracts a positively charged surface on talin-FERM and simultaneously repels the negatively charged surface on talin-RS. Such an electrostatic "pull-push" process promotes the relief of the dual inhibition of talin-FERM, which differs from the classic "steric clash" model for conventional PIP2-induced FERM domain activation. These data therefore unravel a new type of membrane-dependent FERM domain regulation and illustrate how it mediates the talin on/off switches to regulate integrin transmembrane signaling and cell adhesion.

show abstract

“…Among the membrane proteins (MPs) that require a helixassembly to function are ion channels, 1 GPCR membrane receptors 2 and integrins. 3 To probe the complex association of many a-helices, the dimerization of two a-helices is typically used as a case study. Understanding the factors determining helix-helix packing has therefore been the aim of several studies.…”

Section: Introductionmentioning

confidence: 99%

Lipid mediated packing of transmembrane helices – a dissipative particle dynamics study

Benjamini

Smit

2013

Soft Matter

View full text Add to dashboard Cite

Interactions of transmembrane (TM) helices play a key role in many cell processes. The configuration and cross angle these helices adopt are traditionally attributed to specific residue interactions. We present a different approach, in which specific residues are disregarded, and the role of the membrane in TM helix packing is investigated. We introduce a coarse-grained model of TM helices and obtain their characteristic configurations in the membrane both as a single helix and as paired helices. Our analysis shows that hydrophobic mismatch has a substantial effect in determining not only the tilt angles of TM helices but also the cross angles between helix pairs, for a large range of hydrophobic mismatches. We discuss the origin of this effect as well as the deviations from the common trend. Additionally, we explore the effect of hydrophobic mismatch on the Potential of Mean Force (PMF) between TM helices and discuss the importance of helical geometry in forming crossed configurations. Our observations suggest that hydrophobic mismatch must be taken into account when analyzing configurations of TM helix pairs. Hydrophobic mismatch through its effect on helix tilt can explain many cross-angle distribution features, making the role of specific interactions in determining helix pair configurations less significant.

show abstract

Integrins as therapeutic targets: lessons and opportunities

Cited by 402 publications

References 201 publications

Integrin Regulation during Leukocyte Recruitment

Integrin Regulation during Leukocyte Recruitment

A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion

Lipid mediated packing of transmembrane helices – a dissipative particle dynamics study

Contact Info

Product

Resources

About