Recreation of the terminal events in physiological integrin activation

Ye, Feng; Hu, Guiqing; Taylor, David; Ratnikov, Boris I.; Bobkov, Andrey A.; McLean, Mark A.; Sligar, Stephen G.; Taylor, Kenneth A.; Ginsberg, Mark H.

doi:10.1083/jcb.200908045

Cited by 228 publications

(312 citation statements)

References 84 publications

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“…This intermediate conformation of αLβ2 requires Talin-1, suggesting that the initial contact with ICAM-1 is Kindlin-3-independent, whereas further conformational changes associated with the high-affinity state are Kindlin-3-dependent (29). A similar finding also has been reported for αIIbβ3 integrin binding to fibrinogen, which occurs in the presence of Talin-1 alone (30).…”

Section: Discussionsupporting

confidence: 67%

Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

Moretti

Moser

Lyck

et al. 2013

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

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Activated T cells use very late antigen-4/α4β1 integrin for capture, rolling on, and firm adhesion to endothelial cells, and use leukocyte function-associated antigen-1/αLβ2 integrin for subsequent crawling and extravasation. Inhibition of α4β1 is sufficient to prevent extravasation of activated T cells and is successfully used to combat autoimmune diseases, such as multiple sclerosis. Here we show that effector T cells lacking the integrin activator Kindlin-3 extravasate and induce experimental autoimmune encephalomyelitis in mice immunized with autoantigen. In sharp contrast, adoptively transferred autoreactive T cells from Kindlin-3-deficient mice fail to extravasate into the naïve CNS. Mechanistically, autoreactive Kindlin-3-null T cells extravasate when the CNS is inflamed and the brain microvasculature expresses high levels of integrin ligands. Flow chamber assays under physiological shear conditions confirmed that Kindlin-3-null effector T cells adhere to high concentrations of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, albeit less efficiently than WT T cells. Although these arrested T cells polarize and start crawling, only few remain firmly adherent over time. Our data demonstrate that the requirement of Kindlin-3 for effector T cells to induce α4β1 and αLβ2 integrin ligand binding and stabilization of integrin-ligand bonds is critical when integrin ligand levels are low, but of less importance when integrin ligand levels are high.integrin affinity | EAE

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Section: Discussionsupporting

confidence: 67%

Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

Moretti

Moser

Lyck

et al. 2013

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

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“…Talin plays a major role in both integrin affinity modulation and integrin-actin cytoskeleton linkage (5,(7)(8)(9)(10)(11)(12)(13), and the subcellular localization of talin is important in controlling these biological functions. Yet, our understanding of how the activity of talin is regulated remains incomplete.…”

Section: Discussionmentioning

confidence: 99%

“…Affinity modulation of integrins for their ligands and the connection of most integrins to the actin cytoskeleton are mediated by adaptors that bind to the integrin cytoplasmic domains (1)(2)(3)(4). Among the numerous proteins that associate with integrin cytoplasmic domains, talin has emerged as a central player in both affinity modulation and integrin-actin cytoskeleton linkage (5)(6)(7)(8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

Subcellular Localization of Talin Is Regulated by Inter-domain Interactions

Banno

Goult

Lee

et al. 2012

Journal of Biological Chemistry

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Background: Talin regulates integrin affinity and nucleates the integrin-cytoskeleton linkage at the plasma membrane. Results: Specific inter-domain interactions between the talin head and two rod regions block interaction with actin or plasma membrane localization. Conclusion: Autoinhibitory interactions between the talin head and rod domains maintain cytosolic talin. Significance: Structurally defined inter-domain interactions regulate talin localization and function.

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“…For example, talin and kindlin binding to the integrin cytoplasmic domain was associated with an extended integrin conformation. [28][29][30][31] The observed integrin receptors on the platelet surface allowed us to address the question of integrin conformation. We measured the distance between the globular head domain of individual integrins and the cell membrane (Fig.…”

Section: Zooming Into Intact Platelets With Cryo-electron Tomographymentioning

confidence: 99%

Toward correlating structure and mechanics of platelets

Sorrentino

Studt

Horev

et al. 2016

Cell Adhesion & Migration

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The primary physiological function of blood platelets is to seal vascular lesions after injury and form hemostatic thrombi in order to prevent blood loss. This task relies on the formation of strong cellular-extracellular matrix interactions in the subendothelial lesions. The cytoskeleton of a platelet is key to all of its functions: its ability to spread, adhere and contract. Despite the medical significance of platelets, there is still no high-resolution structural information of their cytoskeleton. Here, we discuss and present 3-dimensional (3D) structural analysis of intact platelets by using cryoelectron tomography (cryo-ET) and atomic force microscopy (AFM). Cryo-ET provides in situ structural analysis and AFM gives stiffness maps of the platelets. In the future, combining highresolution structural and mechanical techniques will bring new understanding of how structural changes modulate platelet stiffness during activation and adhesion.

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Recreation of the terminal events in physiological integrin activation

Abstract: In vitro analysis confirms talin binding is sufficient for activation and extension of membrane-embedded integrin.

Cited by 228 publications

References 84 publications

Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

Subcellular Localization of Talin Is Regulated by Inter-domain Interactions

Toward correlating structure and mechanics of platelets

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