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

2016 ◽  
Author(s):  
Vinay Swaminathan ◽  
Joseph Mathew Kalappurakkal ◽  
Shalin B. Mehta ◽  
Pontus Nordenfelt ◽  
Travis I. Moore ◽  
...  
Keyword(s):  
Focal Adhesions ◽  
Leading Edge ◽  
Αvβ3 Integrin ◽  
Retrograde Flow ◽  
Molecular Scaffold ◽  
Transmembrane Receptors ◽  
Cell Adhesion And Migration ◽  
Mediate Cell Adhesion ◽  
Mediate Cell ◽  
And Migration

Integrins are transmembrane receptors that, upon activation, bind extracellular matrix (ECM) or cell surface ligands and link them to the actin cytoskeleton to mediate cell adhesion and migration1,2. One model for the structural transitions mediating integrin activation termed “the cytoskeletal force hypothesis” posits that force transmitted from the cytoskeleton to ligand-bound integrins acts as an allosteric stabilizer of the extended-open, high-affinity state3. Since cytoskeletal forces in migrating cells are generated by centripetal “retrograde flow” of F-actin from the cell leading edge, where integrin-based adhesions are initiated4,5, this model predicts that F-actin flow should align and orient activated, ligand-bound integrins in integrin-based adhesions. Here, polarization-sensitive fluorescence microscopy of GFP-αVβ3 integrin chimeras in migrating fibroblasts shows that integrins are aligned with respect to the axis of FAs and the direction of F-actin flow, and this alignment requires binding immobilized ligand and talin-mediated linkage to a flowing cytoskeleton. Polarization imaging and Rosetta modelling of chimeras engineered to orient GFP differentially with respect to the integrin headpiece suggest that ligand-bound αVβ3 integrin may be markedly tilted by the force of F-actin flow. These results show that actin cytoskeletal forces actively sculpt an anisotropic molecular scaffold in FAs that may underlie the ability of cells to sense directional ECM and physical cues.

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

2017 ◽  
Vol 114 (40) ◽  
pp. 10648-10653 ◽  
Author(s):  
Vinay Swaminathan ◽  
Joseph Mathew Kalappurakkal ◽  
Shalin B. Mehta ◽  
Pontus Nordenfelt ◽  
Travis I. Moore ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Retrograde Flow ◽  
Molecular Scaffold ◽  
Cell Adhesion And Migration ◽  
Αvβ3 Integrins ◽  
Mediate Cell ◽  
And Migration ◽  
Migrating Cells

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 contractility-driven “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.

scholarly journals Hyperphosphorylated FAK Delocalizes from Focal Adhesions to Membrane Ruffles

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Abdelkader Hamadi ◽  
Therese B. Deramaudt ◽  
Kenneth Takeda ◽  
Philippe Rondé
Keyword(s):  
Tumor Metastasis ◽  
Focal Adhesions ◽  
Downstream Signaling ◽  
Astrocytoma Cells ◽  
Src Inhibitor ◽  
Human Astrocytoma ◽  
Cell Adhesion And Migration ◽  
And Migration ◽  
Downstream Signaling Pathway ◽  
Human Astrocytoma Cells

Cell adhesion and migration are key determinants in tumor metastasis. Adherence of tumor cell to the extracellular matrix is mediated via integrin containing focal adhesions (FAs). Binding of integrins to ECM triggers phosphorylation of two major components of FAs, focal adhesion kinase (FAK) and Src, activating downstream signaling pathway which leads to FA disassembly and cell migration. In this paper, we analyze how phosphorylation of FAK regulates its trafficking at FAs in living human astrocytoma cells. Upon pervanadate-induced FAK phosphorylation, phosphorylated FAK appeared highly expressed at newly formed membrane ruffles. This effect was abolished in presence of the specific Src inhibitor PP2. Our findings demonstrate that upon phosphorylation, FAK delocalizes from FAs to membrane ruffles.

scholarly journals Integrin Signaling as a Cancer Drug Target

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Erik H. J. Danen
Keyword(s):  
Intracellular Signaling ◽  
Therapy Resistance ◽  
Cancer Drug ◽  
Integrin Signaling ◽  
Transmembrane Receptors ◽  
Proliferation And Differentiation ◽  
Mediate Cell Adhesion ◽  
Mediate Cell ◽  
Therapy Strategies

Integrins are transmembrane receptors that mediate cell adhesion to neighboring cells and to the extracellular matrix. Here, the various modes in which integrin-mediated adhesion regulates intracellular signaling pathways impinging on cell survival, proliferation, and differentiation are considered. Subsequently, evidence that integrins also control crucial signaling cascades in cancer cells is discussed. Lastly, the important role of integrin signaling in tumor cells as well as in stromal cells that support cancer growth, metastasis, and therapy resistance indicates that integrin signaling may be an attractive target for (combined) cancer therapy strategies. Current approaches to target integrins in this context are reviewed.

scholarly journals PAK4 methylation by the methyltransferase SETD6 attenuates cell adhesion

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zlata Vershinin ◽  
Michal Feldman ◽  
Dan Levy
Keyword(s):  
Cell Adhesion ◽  
Mammalian Cells ◽  
Focal Adhesions ◽  
Vital Role ◽  
Migration And Invasion ◽  
Wild Type ◽  
Set Domain ◽  
Cell Adhesion And Migration ◽  
P21 Activated Kinase ◽  
And Migration

Abstract P21-activated kinase 4 (PAK4), a member of serine/threonine kinases family is over-expressed in numerous cancer tumors and is associated with oncogenic cell proliferation, migration and invasion. Our recent work demonstrated that the SET-domain containing protein 6 (SETD6) interacts with and methylates PAK4 at chromatin in mammalian cells, leading to activation of the Wnt/β-catenin signaling pathway. In our current work, we identified lysine 473 (K473) on PAK4 as the primary methylation site by SETD6. Methylation of PAK4 at K473 activates β-catenin transcriptional activity and inhibits cell adhesion. Specific methylation of PAK4 at K473 also attenuates paxillin localization to focal adhesions leading to overall reduction in adhesion-related features, such as filopodia and actin structures. The altered adhesion of the PAK4 wild-type cells is accompanied with a decrease in the migrative and invasive characteristics of the cells. Taken together, our results suggest that methylation of PAK4 at K473 plays a vital role in the regulation of cell adhesion and migration.

Regulation of cell migration by α4 and α9 integrins

2019 ◽  
Vol 476 (4) ◽  
pp. 705-718 ◽  
Author(s):  
Willow Hight-Warburton ◽  
Maddy Parsons
Keyword(s):  
Cell Migration ◽  
Expression Profiles ◽  
Focal Adhesions ◽  
Cell Types ◽  
Tissue Expression ◽  
Signalling Pathways ◽  
Adherent Cell ◽  
Transmembrane Receptors ◽  
Binding Partners ◽  
And Migration

Abstract Integrins are heterodimeric transmembrane receptors that play an essential role in enabling cells to sense and bind to extracellular ligands. Activation and clustering of integrins leads to the formation of focal adhesions at the plasma membrane that subsequently initiate signalling pathways to control a broad range of functional endpoints including cell migration, proliferation and survival. The α4 and α9 integrins form a small sub-family of receptors that share some specific ligands and binding partners. Although relatively poorly studied compared with other integrin family members, emerging evidence suggests that despite restricted cell and tissue expression profiles, these integrins play a key role in the regulation of signalling pathways controlling cytoskeletal remodelling and migration in both adherent and non-adherent cell types. This review summarises the known shared and specific roles for α4 and α9 integrins and highlights the importance of these receptors in controlling cell migration within both homeostatic and disease settings.

scholarly journals Does cellular adaptation to force loading rate determine the biphasic vs monotonic response of actin retrograde flow with substrate rigidity?

2021 ◽  
Author(s):  
Partho Sakha De ◽  
Rumi De
Keyword(s):  
Cancer Progression ◽  
Loading Rate ◽  
Focal Adhesions ◽  
Traction Force ◽  
Leading Edge ◽  
Substrate Stiffness ◽  
Retrograde Flow ◽  
Force Loading ◽  
Substrate Rigidity ◽  
Cell Traction

AbstractThe transmission of cytoskeletal forces to the extracellular matrix through focal adhesion complexes is essential for a multitude of biological processes such as cell migration, differentiation, tissue development, cancer progression, among others. During migration, focal adhesions arrest the actin retrograde flow towards the cell interior, allowing the cell front to move forward. Here, we address a puzzling observation of the existence of two distinct phenomena: a biphasic relationship of the retrograde flow and cell traction force with increasing substrate rigidity, with maximum traction force and minimum retrograde flow velocity being present at an optimal substrate stiffness; in contrast, a monotonic relationship between them where the retrograde flow decreases and traction force increases with substrate stiffness. We propose a theoretical model for cell-matrix adhesions at the leading edge of a migrating cell, incorporating a novel approach in force loading rate sensitive binding and reinforcement of focal adhesions assembly and the subsequent force-induced slowing down of actin flow. Our model unravels both biphasic and monotonic responses of the retrograde flow and cell traction force with increasing substrate rigidity, owing to the cell’s ability to sense and adapt to the fast-growing forces. Moreover, we also elucidate how the viscoelastic properties of the substrate regulate these nonlinear responses and alter cellular behaviours.

New potent αvβ3 integrin ligands based on azabicycloalkane (γ,α)-dipeptide mimics

2016 ◽  
Vol 14 (12) ◽  
pp. 3221-3233 ◽  
Author(s):  
M. Pilkington-Miksa ◽  
E. M. V. Araldi ◽  
D. Arosio ◽  
L. Belvisi ◽  
M. Civera ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Αvβ3 Integrin ◽  
Cell Adhesion And Migration ◽  
Integrin Ligands ◽  
And Migration ◽  
Integrin Ligand

A novel promising integrin ligand based on an azabicycloalkane scaffold is able to inhibit both cell adhesion and migration without evidence of toxicity.

scholarly journals Filopodome mapping identifies p130Cas as a mechanosensitive regulator of filopodia stability

2018 ◽  
Author(s):  
Guillaume Jacquemet ◽  
Rafael Saup ◽  
Hellyeh Hamidi ◽  
Mitro Miihkinen ◽  
Johanna Ivaska
Keyword(s):  
Binding Sites ◽  
Focal Adhesions ◽  
Structure And Function ◽  
Structured Illumination ◽  
Structured Illumination Microscopy ◽  
Cell Adhesion And Migration ◽  
And Migration ◽  
Cellular Behaviour ◽  
And Function ◽  
Fine Tune

AbstractFilopodia are adhesive cellular protrusions specialised in the detection of extracellular matrix (ECM)-derived cues. While ECM engagement at focal adhesions is known to trigger the recruitment of hundreds of proteins (“adhesome”) to fine-tune cellular behaviour, the components of the filopodia adhesions remain undefined. Here, we performed a structured illumination microscopy-based screen to map the localisation of 80 target proteins, linked to cell adhesion and migration, within filopodia. We demonstrate preferential enrichment of several adhesion proteins to either filopodia tips, filopodia shafts, or shaft subdomains suggesting divergent, spatially restricted functions for these proteins. Moreover, proteins with phospho-inositide (PI) binding sites are particularly enriched in filopodia. This, together with the strong localisation of PI(3,4)P2 in filopodia tips, predicts critical roles for PIs in regulating filopodia ultra-structure and function. Our mapping further reveals that filopodia adhesions consist of a unique set of proteins, the filopodome, that are distinct from classical nascent adhesions, focal adhesions and fibrillar adhesions. Using live imaging, we observe that filopodia adhesions can give rise to nascent adhesions, which, in turn, form focal adhesions. Finally, we demonstrate that p130Cas (BCAR1) is recruited to filopodia tips via its CCHD domain and acts as a mechanosensitive regulator of filopodia stability.

scholarly journals Hypoxia-inducible Factor Regulates αvβ3 Integrin Cell Surface Expression

2005 ◽  
Vol 16 (4) ◽  
pp. 1901-1912 ◽  
Author(s):  
Karen D. Cowden Dahl ◽  
Sarah E. Robertson ◽  
Valerie M. Weaver ◽  
M. Celeste Simon
Keyword(s):  
Cell Surface ◽  
Cell Fate ◽  
Hypoxia Inducible Factor ◽  
Focal Adhesions ◽  
Surface Expression ◽  
Melanoma Cells ◽  
Cell Surface Expression ◽  
Migration And Invasion ◽  
Αvβ3 Integrin ◽  
And Migration

Hypoxia-inducible factor (HIF)-deficient placentas exhibit a number of defects, including changes in cell fate adoption, lack of fetal angiogenesis, hypocellularity, and poor invasion into maternal tissue. HIF is a heterodimeric transcription factor consisting of α and β aryl hydrocarbon receptor nuclear translocator or ARNT) subunits. We used undifferentiated trophoblast stem (TS) cells to characterize HIF-dependent adhesion, migration, and invasion. Arnt-/- and Hifα-/- TS cells exhibit reduced adhesion and migration toward vitronectin compared with wild-type cells. Furthermore, this defect is associated with decreased cell surface expression of integrin αvβ3 and significantly decreased expression of this integrin in focal adhesions. Because of the importance of adhesion and migration in tumor progression (in addition to placental development), we examined the affect of culturing B16F0 melanoma cells in 1.5% oxygen (O2). Culturing B16F0 melanoma cells at 1.5% O2 resulted in increased αvβ3 integrin surface expression and increased adhesion to and migration toward vitronectin. Together, these data suggest that HIF and O2 tension influence placental invasion and tumor migration by increasing cell surface expression of αvβ3 integrin.

scholarly journals αvβ3 integrin spatially regulates VASP and RIAM to control adhesion dynamics and migration

2010 ◽  
Vol 189 (2) ◽  
pp. 369-383 ◽  
Author(s):  
Daniel C. Worth ◽  
Kairbaan Hodivala-Dilke ◽  
Stephen D. Robinson ◽  
Samantha J. King ◽  
Penny E. Morton ◽  
...  
Keyword(s):  
Regulatory Protein ◽  
Focal Adhesions ◽  
Αvβ3 Integrin ◽  
Β1 Integrin ◽  
Downstream Signaling ◽  
Β3 Integrin ◽  
And Migration ◽  
2D And 3D

Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of β3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of β3 integrin results in a loss of protein kinase A–dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in β3-null cells is preferentially associated with Rap1-GTP–interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP–RIAM complex at focal adhesions and subsequent increased binding of talin to β1 integrin. These data demonstrate a novel mechanism by which αvβ3 integrin acts to locally suppress β1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration.

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