Direction of actin flow dictates integrin LFA-1 orientation during leukocyte migration

Nordenfelt, Pontus; Moore, Travis I.; Mehta, Shalin B.; Kalappurakkal, Joseph Mathew; Swaminathan, Vinay; Koga, Nobuyasu; Lambert, Talley J.; Baker, David; Waters, Jennifer; Oldenbourg, Rudolf; Tani, Tomomi; Mayor, Satyajit; Waterman, Clare M.; Springer, Timothy A.

doi:10.1038/s41467-017-01848-y

Cited by 92 publications

(100 citation statements)

References 58 publications

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“…4I). Additionally, the coalignment and tilting of integrins is not specific for αVβ3 or other FN binding integrins, as a concurrent study shows a similar organization for the LFA-1/αLβ2 integrins in migrating T cells (33,34).…”

Section: Discussionmentioning

confidence: 90%

Actin retrograde flow actively aligns and orients ligand-engaged integrins in focal adhesions

Swaminathan

Kalappurakkal

Mehta

et al. 2017

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

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104

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Integrins are transmembrane receptors that, upon activation, bind extracellular ligands and link them to the actin filament (F-actin) cytoskeleton to mediate cell adhesion and migration. Cytoskeletal forces in migrating cells generated by polymerization-or contractilitydriven "retrograde flow" of F-actin from the cell leading edge have been hypothesized to mediate integrin activation for ligand binding. This predicts that these forces should align and orient activated, ligand-bound integrins at the leading edge. Here, polarization-sensitive fluorescence microscopy of GFP-αVβ3 integrins in fibroblasts shows that integrins are coaligned in a specific orientation within focal adhesions (FAs) in a manner dependent on binding immobilized ligand and a talin-mediated linkage to the F-actin cytoskeleton. These findings, together with Rosetta modeling, suggest that integrins in FA are coaligned and may be highly tilted by cytoskeletal forces. Thus, the F-actin cytoskeleton sculpts an anisotropic molecular scaffold in FAs, and this feature may underlie the ability of migrating cells to sense directional extracellular cues.cell migration | mechanosensing | fluorescence polarization microscopy

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Section: Discussionmentioning

confidence: 90%

Actin retrograde flow actively aligns and orients ligand-engaged integrins in focal adhesions

Swaminathan

Kalappurakkal

Mehta

et al. 2017

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

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104

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“…The integrin LFA-1 (lymphocyte function-associated antigen 1) form complexes with intercellular adhesion molecule-1 (ICAM-1) and sIGSF member cluster of differentiation 2 (CD2) with human CD58 (hCD58) in the context of T cell effector function (5). Integrin-mediated adhesion is an active process regulated by interactions with the F-actin transport network (6), whereas the sIGSF members operate through highly multivalent microdomains and are less dependent on cellular energy (7). When a live T cell forms an interface with a planar supported lipid bilayer (SLB) containing freely mobile ICAM-1, CD58 and pMHC, the individual complexes are organized into a layered, radially symmetrical pattern with central TCR-pMHC cluster (synaptic cleft and central supramolecular activation cluster, cSMAC), surrounded by an integrin adhesion ring (peripheral or pSMAC), and fringed by sIGSF microdomains in the distal SMAC (dSMAC), resembling flower petals known as corolla (5,(8)(9)(10)(11).…”

Section: [Main Text: ] Introductionmentioning

confidence: 99%

In silico characterization of mechanisms positioning costimulatory and checkpoint complexes in immune synapses

Siokis

Robert

Demetriou

et al. 2020

Preprint

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One Sentence Summary: Computer simulations of immunological synapses reveal the localization mechanisms of immunoglobulin superfamily adhesion and costimulatory/checkpoint complexes.Abstract: Integrin and small immunoglobulin superfamily (sIGSF) adhesion complexes function physiologically in human immunological synapses (IS) wherein sIGSF complexes form a corolla of microdomains around an integrin ring and secretory core. The corolla recruits and retains the major costimulatory and checkpoint complexes that regulate the response to T cell receptor (TCR) engagement, making forces that govern corolla formation of particular interest. We developed a phenomenological agent-based model in order to test different hypotheses concerning the mechanisms underlying molecular reorganization during IS formation. The model showed that sIGSF complexes are passively excluded to the distal aspect of the IS as long as their interaction with the ramified F-actin transport network is absent or weaker than that of integrins. An attractive force between sIGSF adhesion and costimulatory/checkpoint complexes relocates the latter from the centre of the IS to the corolla. The simulations suggest that size based sorting interactions with large glycocalyx components as well as a short-range selfattraction between sIGSF complexes explain the corolla "petals". These molecular and mechanistic features establish a general model that can recapitulate complex pattern formation processes observed in cell-bilayer and cell-cell interfaces.

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“…The ability of integrins to sense and respond to force is essential for cell shape, tissue architecture, cell migration and other fundamental processes. In the vasculature, the influence of flow on EC physiology involves shear stress-mediated activation of integrins (Tzima et al, 2001), which engage with extracellular matrix thereby triggering outside-in signalling (Bhullar et al, 1998;Chen et al, 2015;Chen et al, 1999;Jalali et al, 2001;Orr et al, 2006;Orr et al, 2005;Shyy and Chien, 2002;Tzima et al, 2001). Activation of a5b1 integrins by shear stress leads to Ca 2+ signalling (Buschmann et al, 2010;Loufrani et al, 2008;Matthews et al, 2006;Thodeti et al, 2009;Yang et al, 2011), which in turn promotes vascular quiescence and health (Urbich et al, 2002) (Urbich et al, 2000) (Luu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

β1 integrin is a sensor of blood flow direction

Xanthis

Souilhol

Serbanovic-Canic

et al. 2019

Preprint

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Running title: b1 integrin senses blood flow direction. SUMMARY STATEMENTWe demonstrate using flow systems, magnetic tweezers and knockout mice that β1 integrin is a sensor of shear stress direction in endothelial cells. b1 integrin is activated by unidirectional hemodynamic shear force leading to calcium signalling and cell alignment, but it is not activated by bidirectional force. ABSTRACTThe ability of endothelial cells (EC) to sense blood flow direction is a critical determinant of vascular health and disease. Unidirectional flow induces EC alignment and vascular homeostasis, whereas bidirectional flow has pathophysiological effects. EC express several mechanoreceptors that can respond to fluid flow (shear stress) but the mechanism for sensing the direction of shearing force is poorly understood. We observed using in vitro flow systems and magnetic tweezers that β1 integrin is a key sensor of force direction because it is activated by unidirectional but not bidirectional shearing forces. Consistently, β1 integrin was essential for Ca 2+ signalling and cell alignment in response to unidirectional but not bidirectional shear stress. b1 integrin activation by unidirectional force was amplified in EC that were pre-sheared in the same direction, indicating that alignment and b1 integrin activity has a feedforward interaction which is a hallmark of system stability. En face staining and EC-specific genetic deletion studies of the murine aorta revealed that β1 integrin is activated and is essential for EC alignment at sites of unidirectional flow but is not activated at sites of bidirectional flow. In summary, b1 integrin sensing of unidirectional force is a key mechanism for decoding blood flow mechanics to promote vascular homeostasis.

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Direction of actin flow dictates integrin LFA-1 orientation during leukocyte migration

Cited by 92 publications

References 58 publications

Actin retrograde flow actively aligns and orients ligand-engaged integrins in focal adhesions

Actin retrograde flow actively aligns and orients ligand-engaged integrins in focal adhesions

In silico characterization of mechanisms positioning costimulatory and checkpoint complexes in immune synapses

β1 integrin is a sensor of blood flow direction

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