scholarly journals Stiffness Sensing and Cell Motility: Durotaxis and Contact Guidance

2018 ◽  
Author(s):  
Jingchen Feng ◽  
Herbert Levine ◽  
Xiaoming Mao ◽  
Leonard M. Sander
Keyword(s):  
Mechanical Properties ◽  
Cell Migration ◽  
Cell Motility ◽  
Prior Knowledge ◽  
Focal Adhesions ◽  
Lattice Models ◽  
Vital Role ◽  
Substrate Stiffness ◽  
Contact Guidance ◽  
A Cell

AbstractMechanical properties of the substrate plays a vital role in cell motility. Cells are shown to migrate up stiffness gradient (durotaxis) and along aligned fibers in the substrate (contact guidance). Here we present a simple mechanical model for cell migration, by placing a cell on lattice models for biopolymer gels and hydrogels. In our model cells attach to the substrate via focal adhesions (FAs). As the cells contract, forces are generated at the FAs, determining their maturation and detachment. At the same time, the cell also allowed to move and rotate to maintain force and torque balance. Our model, in which the cells only take the information of forces at the FAs, without a prior knowledge of the substrate stiffness or geometry, is able to reproduce both durotaxis and contact guidance.

Cell motility, contact guidance, and durotaxis

Soft Matter ◽  
2019 ◽  
Vol 15 (24) ◽  
pp. 4856-4864 ◽  
Author(s):  
Jingchen Feng ◽  
Herbert Levine ◽  
Xiaoming Mao ◽  
Leonard M. Sander
Keyword(s):  
Mechanical Properties ◽  
Cell Motility ◽  
Vital Role ◽  
Contact Guidance

Mechanical properties of the substrate play a vital role in cell motility.

Substrate Stiffness Affects Laminin-332 Matrix Deposition in Cultured Keretinocytes

2007 ◽  
Author(s):  
Abel L. Thangawng ◽  
Rodney S. Ruoff ◽  
Jonathan C. Jones ◽  
Matthew R. Glucksberg
Keyword(s):  
Mechanical Properties ◽  
Extracellular Matrix ◽  
Cell Motility ◽  
Substrate Stiffness ◽  
Mechanical Environment ◽  
Matrix Deposition ◽  
Laminin 332 ◽  
Substrate Influence

It has been reported that the mechanical properties of a substrate influence cell motility, morphology, and adhesion [1–3]. This work is an attempt to move a step further beyond cells’ sensing the mechanical properties of their environment, by determining whether the secretion and assembly of laminin extracellular matrix is regulated by the mechanical environment in which the cell is placed. We hypothesize that this matrix then influences the behavior of the cell, particularly with regard to its motility.

scholarly journals Shc and Fak Differentially Regulate Cell Motility and Directionality Modulated by Pten

1999 ◽  
Vol 146 (2) ◽  
pp. 389-404 ◽  
Author(s):  
Jianguo Gu ◽  
Masahito Tamura ◽  
Roumen Pankov ◽  
Erik H.J. Danen ◽  
Takahisa Takino ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Suppressor ◽  
Cell Motility ◽  
Map Kinase ◽  
Focal Adhesion ◽  
Focal Adhesions ◽  
Dominant Negative ◽  
Kinase Activation ◽  
Protein Map ◽  
Mitogen Activated Protein

Cell migration is modulated by regulatory molecules such as growth factors, oncogenes, and the tumor suppressor PTEN. We previously described inhibition of cell migration by PTEN and restoration of motility by focal adhesion kinase (FAK) and p130 Crk-associated substrate (p130Cas). We now report a novel pathway regulating random cell motility involving Shc and mitogen-activated protein (MAP) kinase, which is downmodulated by PTEN and additive to a FAK pathway regulating directional migration. Overexpression of Shc or constitutively activated MEK1 in PTEN- reconstituted U87-MG cells stimulated integrin- mediated MAP kinase activation and cell migration. Conversely, overexpression of dominant negative Shc inhibited cell migration; Akt appeared uninvolved. PTEN directly dephosphorylated Shc. The migration induced by FAK or p130Cas was directionally persistent and involved extensive organization of actin microfilaments and focal adhesions. In contrast, Shc or MEK1 induced a random type of motility associated with less actin cytoskeletal and focal adhesion organization. These results identify two distinct, additive pathways regulating cell migration that are downregulated by tumor suppressor PTEN: one involves Shc, a MAP kinase pathway, and random migration, whereas the other involves FAK, p130Cas, more extensive actin cytoskeletal organization, focal contacts, and directionally persistent cell motility. Integration of these pathways provides an intracellular mechanism for regulating the speed and the directionality of cell migration.

scholarly journals Loss of Ena/VASP interferes with lamellipodium architecture, motility and integrin-dependent adhesion

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Julia Damiano-Guercio ◽  
Laëtitia Kurzawa ◽  
Jan Mueller ◽  
Georgi Dimchev ◽  
Matthias Schaks ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Actin Filaments ◽  
Focal Adhesions ◽  
Protein Accumulation ◽  
Actin Assembly ◽  
Filament Length ◽  
Capping Protein ◽  
Network Geometry ◽  
Positive Regulators

Cell migration entails networks and bundles of actin filaments termed lamellipodia and microspikes or filopodia, respectively, as well as focal adhesions, all of which recruit Ena/VASP family members hitherto thought to antagonize efficient cell motility. However, we find these proteins to act as positive regulators of migration in different murine cell lines. CRISPR/Cas9-mediated loss of Ena/VASP proteins reduced lamellipodial actin assembly and perturbed lamellipodial architecture, as evidenced by changed network geometry as well as reduction of filament length and number that was accompanied by abnormal Arp2/3 complex and heterodimeric capping protein accumulation. Loss of Ena/VASP function also abolished the formation of microspikes normally embedded in lamellipodia, but not of filopodia capable of emanating without lamellipodia. Ena/VASP-deficiency also impaired integrin-mediated adhesion accompanied by reduced traction forces exerted through these structures. Our data thus uncover novel Ena/VASP functions of these actin polymerases that are fully consistent with their promotion of cell migration.

scholarly journals Activation of cell migration via morphological changes in focal adhesions depends on shear stress in MYCN-amplified neuroblastoma cells

2019 ◽  
Vol 16 (152) ◽  
pp. 20180934
Author(s):  
Takumi Hiraiwa ◽  
Takahiro G. Yamada ◽  
Norihisa Miki ◽  
Akira Funahashi ◽  
Noriko Hiroi
Keyword(s):  
Shear Stress ◽  
Cell Migration ◽  
Cell Motility ◽  
Morphological Changes ◽  
Neuroblastoma Cell ◽  
Neuroblastoma Cells ◽  
Focal Adhesions ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
The Relationship

Neuroblastoma is the most common solid tumour of childhood, and it metastasizes to distant organs. However, the mechanism of metastasis, which generally depends on the cell motility of the neuroblastoma, remains unclear. In many solid tumours, it has been reported that shear stress promotes metastasis. Here, we investigated the relationship between shear stress and cell motility in the MYCN-amplified human neuroblastoma cell line IMR32, using a microfluidic device. We confirmed that most of the cells migrated downstream, and cell motility increased dramatically when the cells were exposed to a shear stress of 0.4 Pa, equivalent to that expected in vivo . We observed that the morphological features of focal adhesion were changed under a shear stress of 0.4 Pa. We also investigated the relationship between malignancy and the motility of IMR32 cells under shear stress. Decreasing the expression of MYCN in IMR32 cells via siRNA transfection inhibited cell motility by a shear stress of 0.4 Pa. These results suggest that MYCN-amplified neuroblastoma cells under high shear stress migrate to distant organs due to high cell motility, allowing cell migration to lymphatic vessels and venules.

scholarly journals Focal adhesion-generated cues in extracellular matrix regulate cell migration by local induction of clathrin-coated plaques

2018 ◽  
Author(s):  
Delia Bucher ◽  
Markus Mukenhirn ◽  
Kem A. Sochacki ◽  
Veronika Saharuka ◽  
Christian Huck ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Migration ◽  
Focal Adhesions ◽  
Plaque Formation ◽  
Cell Contact ◽  
Coated Pits ◽  
Independent Manner ◽  
A Cell ◽  
And Function ◽  
Topographical Cues

AbstractClathrin is a unique scaffold protein, which forms polyhedral lattices with flat and curved morphology. The function of curved clathrin-coated pits in forming endocytic structures is well studied. On the contrary, the role of large flat clathrin arrays, called clathrin-coated plaques, remains ambiguous. Previous studies suggested an involvement of plaques in cell adhesion. However, the molecular origin leading to their formation and their precise functions remain to be determined. Here, we study the origin and function of clathrin-coated plaques during cell migration. We revealed that plaque formation is intimately linked to extracellular matrix (ECM) modification by focal adhesions (FAs). We show that in migrating cells, FAs digest the ECM creating extracellular topographical cues that dictate the future location of clathrin-coated plaques. We identify Eps15 and Eps15R as key regulators for the formation of clathrin-coated plaques at locally remodelled ECM sites. Using a genetic silencing approach to abrogate plaque formation and 3D-micropatterns to spatially control the location of clathrin-coated plaques, we could directly correlate cell migration directionality with the formation of clathrin-coated plaques and their ability to recognize extracellular topographical cues. We here define the molecular mechanism regulating the functional interplay between FAs and plaques and propose that clathrin-coated plaques act as regulators of cell migration promoting contact guidance-mediated collective migration in a cell-to-cell contact independent manner.

scholarly journals ARHGAP4-SEPT2-SEPT9 complex enables both up- and down-modulation of integrin-mediated focal adhesions, cell migration, and invasion

2021 ◽  
pp. mbc.E21-01-0010
Author(s):  
Kang Na ◽  
Tsubasa S. Matsui ◽  
Liu Shiyou ◽  
Shinji Deguchi
Keyword(s):  
Cell Migration ◽  
Rho Gtpase ◽  
Focal Adhesions ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Cell Migration And Invasion ◽  
Phenotypic Changes ◽  
Gtpase Activating Proteins ◽  
A Cell ◽  
Rho Family

The Rho family of GTPases are inactivated in a cell context-dependent manner by Rho-GTPase-activating proteins (Rho-GAPs), but their signaling mechanisms are poorly understood. Here we demonstrate that ARHGAP4, the Rho-GAPs, forms a complex with SEPT2 and SEPT9 via its Rho-GAP domain and SH3 domain to enable both up- and down-modulation of integrin-mediated focal adhesions (FAs). We show that silencing ARHGAP4 as well as overexpressing its two mutually independent upstream regulators SEPT2 and SEPT9 all induce reorganization of FAs to newly express Integrin Beta 1 and also enhance both cell migration and invasion. Interestingly, even if these cell migration/invasion-associated phenotypic changes are induced upon perturbations to the complex, it does not necessarily cause enhanced clustering of FAs. Instead, its extent depends on whether the microenvironment contains ligands suitable for the upregulated Integrin Beta 1. These results provide novel insights to cell migration, invasion, and microenvironment-dependent phenotypic changes regulated by the newly identified complex.

scholarly journals Annexin A6 and NPC1 regulate LDL-inducible cell migration and distribution of focal adhesions

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Jaimy Jose ◽  
Monira Hoque ◽  
Johanna Engel ◽  
Syed S. Beevi ◽  
Mohamed Wahba ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Mutant Cell ◽  
Chinese Hamster ◽  
Focal Adhesions ◽  
Migration And Invasion ◽  
3 Dimensional ◽  
Late Endosomes ◽  
Niemann Pick ◽  
Mutant Cells

AbstractCholesterol is considered indispensable for cell motility, but how physiological cholesterol pools enable cells to move forward remains to be clarified. The majority of cells obtain cholesterol from the uptake of Low-Density lipoproteins (LDL) and here we demonstrate that LDL stimulates A431 squamous epithelial carcinoma and Chinese hamster ovary (CHO) cell migration and invasion. LDL also potentiated epidermal growth factor (EGF) -stimulated A431 cell migration as well as A431 invasion in 3-dimensional environments, using organotypic assays. Blocking cholesterol export from late endosomes (LE), using Niemann Pick Type C1 (NPC1) mutant cells, pharmacological NPC1 inhibition or overexpression of the annexin A6 (AnxA6) scaffold protein, compromised LDL-inducible migration and invasion. Nevertheless, NPC1 mutant cells established focal adhesions (FA) that contain activated focal adhesion kinase (pY397FAK, pY861FAK), vinculin and paxillin. Compared to controls, NPC1 mutants display increased FA numbers throughout the cell body, but lack LDL-inducible FA formation at cell edges. Strikingly, AnxA6 depletion in NPC1 mutant cells, which restores late endosomal cholesterol export in these cells, increases their cell motility and association of the cholesterol biosensor D4H with active FAK at cell edges, indicating that AnxA6-regulated transport routes contribute to cholesterol delivery to FA structures, thereby improving NPC1 mutant cell migratory behaviour.

scholarly journals Integrin Crosstalk Modulates Stiffness-independent Motility of CD4+ T Lymphocytes

2021 ◽  
pp. mbc.E21-03-0131
Author(s):  
Sarah Hyun Ji Kim ◽  
Daniel A. Hammer
Keyword(s):  
Mechanical Properties ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Motility ◽  
Cd4 T Cells ◽  
Substrate Stiffness ◽  
Upstream Migration ◽  
Matrix Stiffness ◽  
Static Conditions

To carry out their physiological responsibilities, CD4+ T lymphocytes interact with various tissues of different mechanical properties. Recent studies suggest that T cells migrate upstream on surfaces expressing ICAM-1 through interaction with LFA-1 integrins. LFA-1 likely interacts as a mechanosensor, and thus we hypothesized that substrate mechanics might affect the ability of LFA-1 to support upstream migration of T cells under flow. Here, we measured motility of CD4+ T lymphocytes on polyacrylamide gels with pre-determined stiffnesses containing ICAM-1, VCAM-1, or 1:1 mixture of VCAM-1/ICAM-1. Under static conditions, we found that CD4+ T cells exhibit an increase in motility on ICAM-1, but not on VCAM-1 or VCAM-1/ICAM-1 mixed, surfaces as a function of matrix stiffness. The mechanosensitivity of T cell motility on ICAM-1 is overcome when VLA-4 is ligated with soluble VCAM-1. Lastly, we observed that CD4+ T cells migrate upstream under flow on ICAM-1-functionalized hydrogels, independent of substrate stiffness. In summary, we show that CD4+ T cells under no flow respond to matrix stiffness through LFA-1, and that the crosstalk of VLA-4 and LFA-1 can compensate for deformable substrates. Interestingly, CD4+ T lymphocytes migrated upstream on ICAM-1 regardless of the substrate stiffness, suggesting that flow can compensate for substrate stiffness.

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