Talin-bound NPLY motif recruits integrin-signaling adapters to regulate cell spreading and mechanosensing

Pinon, Perrine; Pärssinen, Jenita; Vázquez, Patricia; Bachmann, Michael; Rahikainen, Rolle; Jacquier, Marie-Claude; Azizi, Latifeh; Määttä, Juha; Bastmeyer, Martin; Hytönen, Vesa P.; Wehrle-Haller, Bernhard

doi:10.1083/jcb.201308136

Cited by 43 publications

(97 citation statements)

References 76 publications

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“…Consistent with this, β3 tail mutations that resulted in normal integrin activation and talin binding but decreased cell spreading, were recently described (Pinon et al, 2014). A previous study showed that expression of β1-K752L in integrin β1-null fibroblasts did not alter the integrin activation status or the ability of the cells to adhere to fibronectin and laminin-111; however this mutation did inhibit cell spreading and migration (Armulik et al, 2004).…”

Section: Discussionsupporting

confidence: 72%

Implications of the differing roles of the β1 and β3 transmembrane and cytoplasmic domains for integrin function

Mathew

Jiang

et al. 2016

eLife

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Integrins are transmembrane receptors composed of α and β subunits. Although most integrins contain β1, canonical activation mechanisms are based on studies of the platelet integrin, αIIbβ3. Its inactive conformation is characterized by the association of the αIIb transmembrane and cytosolic domain (TM/CT) with a tilted β3 TM/CT that leads to activation when disrupted. We show significant structural differences between β1 and β3 TM/CT in bicelles. Moreover, the ‘snorkeling’ lysine at the TM/CT interface of β subunits, previously proposed to regulate αIIbβ3 activation by ion pairing with nearby lipids, plays opposite roles in β1 and β3 integrin function and in neither case is responsible for TM tilt. A range of affinities from almost no interaction to the relatively high avidity that characterizes αIIbβ3 is seen between various α subunits and β1 TM/CTs. The αIIbβ3-based canonical model for the roles of the TM/CT in integrin activation and function clearly does not extend to all mammalian integrins.DOI: http://dx.doi.org/10.7554/eLife.18633.001

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Section: Discussionsupporting

confidence: 72%

Implications of the differing roles of the β1 and β3 transmembrane and cytoplasmic domains for integrin function

Mathew

Jiang

et al. 2016

eLife

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“…[22][23][24] Talin, a cytoplasmic protein, is known to bind to the cytoplasmic tail of integrin and increase its affinity in response to various agonists acting on platelets. [25,26] Thus, we hypothesized that indothiazinone's antiplatelet activity may be ascribed to its ability to inhibit the function of talin.…”

Section: Effect Of Indothiazinone On Talin-induced Pac1 Bindingmentioning

confidence: 99%

Identification of indothiazinone as a natural antiplatelet agent

et al. 2017

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Cardiovascular disease, which is caused by unregulated platelet aggregation, is one of the main causes of deaths worldwide. Many studies have focused on natural products with antiplatelet effects as a safe alternative therapy to prevent the disease. In this context, an in-house chemical library was screened to find natural products capable of inhibiting the interaction between platelet integrin αIIbβ3 and fibrinogen, which is an essential step in platelet aggregation. On the basis of the screening results, indothiazinone, an alkaloid found in microbial cultures, was identified as a potential antiplatelet agent. Specifically, indothiazinone treatment significantly inhibited the binding of fibrinogen to Chinese hamster ovary cells expressing integrin αIIbβ3. It also restricted thrombin- and adenosine diphosphate-dependent spreading of human platelets on a fibrinogen matrix. More importantly, surface plasmon resonance and molecular dynamics studies suggested that indothiazinone suppressed talin-induced activation of integrin αIIbβ3 presumably by inhibiting talin-integrin interaction. In conclusion, these results suggest that indothiazinone can be used as a lead compound for the development of antiplatelet drugs with a novel mode of action.

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“…Integrin transmembrane proteins and the talin cytoskeletal binding protein play critical roles in cell migration [8]. PI4,5P 2 and PI4,5P 2 synthesizing enzymes control integrin activation by talin in the process termed “inside-out” integrin signaling [74, 75]. Adhesion, spreading and migration are all directly influenced by the activation state of integrins and talin in focal adhesion complexes [74, 75].…”

Section: Pip Kinases Regulate Pi45p2 Effectors In Cell Migrationmentioning

confidence: 99%

“…PI4,5P 2 and PI4,5P 2 synthesizing enzymes control integrin activation by talin in the process termed “inside-out” integrin signaling [74, 75]. Adhesion, spreading and migration are all directly influenced by the activation state of integrins and talin in focal adhesion complexes [74, 75]. PI4,5P 2 generation by a focal adhesion-targeting splice isoform of PIPKIγ, PIPKIγi2, putatively provides a discrete pool of PI4,5P 2 required for talin activation during assembly of focal adhesion complexes [37, 44, 76].…”

Section: Pip Kinases Regulate Pi45p2 Effectors In Cell Migrationmentioning

confidence: 99%

PIP kinases define PI4,5P2 signaling specificity by association with effectors

Choi

Thapa

Tan

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Phosphatidylinositol 4,5-bisphosphate (PI4,5P2) is an essential lipid messenger with roles in all eukaryotes and most aspects of human physiology. By controlling the targeting and activity of its effectors, PI4,5P2 modulates processes, such as cell migration, vesicular trafficking, cellular morphogenesis, signaling and gene expression. In cells, PI4,5P2 has a much higher concentration than other phosphoinositide species and its total content is largely unchanged in response to extracellular stimuli. The discovery of a vast array of PI4,5P2 binding proteins is consistent with data showing that the majority of cellular PI4,5P2 is sequestered. This supports a mechanism where PI4,5P2 functions as a localized and highly specific messenger. Further support of this mechanism comes from the de novo synthesis of PI4,5P2 which is often linked with PIP kinase interaction with PI4,5P2 effectors and is a mechanism to define specificity of PI4,5P2 signaling. The association of PI4,5P2-generating enzymes with PI4,5P2 effectors regulate effector function both temporally and spatially in cells. In this review, the PI4,5P2 effectors whose functions are tightly regulated by associations with PI4,5P2-generating enzymes will be discussed.

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Talin-bound NPLY motif recruits integrin-signaling adapters to regulate cell spreading and mechanosensing

Abstract: β3 integrin residue Y747 is required for cell spreading and paxillin adapter recruitment to substrate-bound integrins in response to substrate stiffness.

Cited by 43 publications

References 76 publications

Implications of the differing roles of the β1 and β3 transmembrane and cytoplasmic domains for integrin function

Implications of the differing roles of the β1 and β3 transmembrane and cytoplasmic domains for integrin function

Identification of indothiazinone as a natural antiplatelet agent

PIP kinases define PI4,5P2 signaling specificity by association with effectors

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