Faculty Opinions recommendation of Rabgap1 promotes recycling of active β1 integrins to support effective cell migration.

2021 ◽  
Author(s):  
Guido Serini ◽  
Donatella Valdembri
Keyword(s):  
Cell Migration ◽  
Β1 Integrins

scholarly journals Compensation mechanism in tumor cell migration

2003 ◽  
Vol 160 (2) ◽  
pp. 267-277 ◽  
Author(s):  
Katarina Wolf ◽  
Irina Mazo ◽  
Harry Leung ◽  
Katharina Engelke ◽  
Ulrich H. von Andrian ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Shape Change ◽  
Proteolytic Degradation ◽  
Amoeboid Movement ◽  
Tumor Cell Migration ◽  
Tumor Dissemination ◽  
Β1 Integrins

Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor–based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of β1 integrins and MT1–matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered β1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis.

scholarly journals β3-Integrins Rather Than β1-Integrins Dominate Integrin-Matrix Interactions Involved in Postinjury Smooth Muscle Cell Migration

Circulation ◽  
1998 ◽  
Vol 97 (18) ◽  
pp. 1818-1827 ◽  
Author(s):  
Marvin J. Slepian ◽  
Stephen P. Massia ◽  
Behrooz Dehdashti ◽  
Anne Fritz ◽  
Luke Whitesell
Keyword(s):  
Smooth Muscle ◽  
Cell Migration ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Matrix Interactions ◽  
Smooth Muscle Cell Migration ◽  
Β1 Integrins

scholarly journals Functional Hierarchy of Simultaneously Expressed Adhesion Receptors: Integrin α2β1 but Not CD44 Mediates MV3 Melanoma Cell Migration and Matrix Reorganization within Three-dimensional Hyaluronan-containing Collagen Matrices

1999 ◽  
Vol 10 (10) ◽  
pp. 3067-3079 ◽  
Author(s):  
Kerstin Maaser ◽  
Katarina Wolf ◽  
C. Eberhard Klein ◽  
Bernd Niggemann ◽  
Kurt S. Zänker ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Tracking ◽  
Three Dimensional ◽  
Focal Adhesions ◽  
Time Lapse ◽  
Computer Assisted ◽  
Adhesion Receptors ◽  
Collagen Matrices ◽  
Β1 Integrins ◽  
Associated Functions

Haptokinetic cell migration across surfaces is mediated by adhesion receptors including β1 integrins and CD44 providing adhesion to extracellular matrix (ECM) ligands such as collagen and hyaluronan (HA), respectively. Little is known, however, about how such different receptor systems synergize for cell migration through three-dimensionally (3-D) interconnected ECM ligands. In highly motile human MV3 melanoma cells, both β1 integrins and CD44 are abundantly expressed, support migration across collagen and HA, respectively, and are deposited upon migration, whereas only β1 integrins but not CD44 redistribute to focal adhesions. In 3-D collagen lattices in the presence or absence of HA and cross-linking chondroitin sulfate, MV3 cell migration and associated functions such as polarization and matrix reorganization were blocked by anti-β1 and anti-α2 integrin mAbs, whereas mAbs blocking CD44, α3, α5, α6, or αv integrins showed no effect. With use of highly sensitive time-lapse videomicroscopy and computer-assisted cell tracking techniques, promigratory functions of CD44 were excluded. 1) Addition of HA did not increase the migratory cell population or its migration velocity, 2) blocking of the HA-binding Hermes-1 epitope did not affect migration, and 3) impaired migration after blocking or activation of β1 integrins was not restored via CD44. Because α2β1-mediated migration was neither synergized nor replaced by CD44–HA interactions, we conclude that the biophysical properties of 3-D multicomponent ECM impose more restricted molecular functions of adhesion receptors, thereby differing from haptokinetic migration across surfaces.

scholarly journals New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2531
Author(s):  
Anna Gorrasi ◽  
Anna Maria Petrone ◽  
Anna Li Santi ◽  
Mariaevelina Alfieri ◽  
Nunzia Montuori ◽  
...  
Keyword(s):  
Cell Migration ◽  
Lipid Rafts ◽  
Ectopic Expression ◽  
Phosphatidyl Inositol ◽  
Dependent Manner ◽  
Hek 293 ◽  
Upa Receptor ◽  
293 Cells ◽  
Β1 Integrins ◽  
Pc3 Cells

The urokinase (uPA) receptor (uPAR) plays a key role in cell migration. We previously showed that uPAR-negative HEK-293 cells efficiently migrate toward serum but, after uPAR ectopic expression, migrate only in a uPAR-dependent manner. In fact, migration of uPAR-transfected HEK-293 (uPAR-293) cells is impaired by anti-uPAR antibodies, without recovery of the uPAR-independent migration mechanisms formerly active. Prostate carcinoma PC3 cells, which express high endogenous uPAR levels, migrated only through a uPAR-dependent mechanism; in fact, the silencing of uPAR expression inhibited their migration. We hypothesize a crucial role of the uPAR glycosyl-phosphatidyl-inositol (GPI) tail, which promotes uPAR partitioning to lipid rafts, in uPAR-controlled cell migration. Here, we show that removal of the uPAR GPI-tail, or lipid rafts disruption by methyl-beta-cyclodextrin impairs migration of PC3 cells, incapable of uPAR-independent migration, whereas it restores uPAR-independent migration in uPAR-293 cells. We then show that, in PC3 cells, both uPAR signaling partners, β1 integrins and receptors for formylated peptides (FPRs), partly associate with lipid rafts. Inhibition of their interaction with uPAR impairs this association and impairs cell migration. Interestingly, blocking uPAR association with FPRs also impairs β1 integrin partitioning to lipid rafts, whereas blocking its association with β1 integrins has no effect on FPRs partitioning. On these bases, we propose that uPAR controls cell migration by connecting β1 integrins and FPRs and, through its GPI tail, by driving them into lipid rafts, thus promoting pro-migratory signals. uPAR-mediated partitioning of integrins to lipid rafts is strictly dependent on uPAR association with FPRs.

scholarly journals Rabgap1 promotes recycling of active β1 integrins to support effective cell migration

2020 ◽  
Vol 133 (18) ◽  
pp. jcs243683
Author(s):  
Anna V. Samarelli ◽  
Tilman Ziegler ◽  
Alexander Meves ◽  
Reinhard Fässler ◽  
Ralph T. Böttcher
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Adhesion Formation ◽  
Migration And Invasion ◽  
Β1 Integrin ◽  
Mouse Fibroblasts ◽  
Endosomal Recycling ◽  
Focal Adhesion Formation ◽  
Β1 Integrins ◽  
Npxy Motif

ABSTRACTIntegrin function depends on the continuous internalization of integrins and their subsequent endosomal recycling to the plasma membrane to drive adhesion dynamics, cell migration and invasion. Here we assign a pivotal role for Rabgap1 (GAPCenA) in the recycling of endocytosed active β1 integrins to the plasma membrane. The phosphotyrosine-binding (PTB) domain of Rabgap1 binds to the membrane-proximal NPxY motif in the cytoplasmic domain of β1 integrin subunits on endosomes. Silencing Rabgap1 in mouse fibroblasts leads to the intracellular accumulation of active β1 integrins, alters focal adhesion formation, and decreases cell migration and cancer cell invasion. Functionally, Rabgap1 facilitates active β1 integrin recycling to the plasma membrane through attenuation of Rab11 activity. Taken together, our results identify Rabgap1 as an important factor for conformation-specific integrin trafficking and define the role of Rabgap1 in β1-integrin-mediated cell migration in mouse fibroblasts and breast cancer cells.

scholarly journals Induction of Cell Scattering by Expression of β1 Integrins in β1-Deficient Epithelial Cells Requires Activation of Members of the Rho Family of Gtpases and Downregulation of Cadherin and Catenin Function

1999 ◽  
Vol 147 (6) ◽  
pp. 1325-1340 ◽  
Author(s):  
Clotilde Gimond ◽  
Arjan van der Flier ◽  
Sanne van Delft ◽  
Cord Brakebusch ◽  
Ingrid Kuikman ◽  
...  
Keyword(s):  
Cell Migration ◽  
Epithelial Cells ◽  
Adherens Junctions ◽  
Interleukin 2 ◽  
Focal Adhesions ◽  
Morphological Transition ◽  
Protein Levels ◽  
Cell Scattering ◽  
Β1 Integrins ◽  
Cell Cell

Adhesion receptors, which connect cells to each other and to the surrounding extracellular matrix (ECM), play a crucial role in the control of tissue structure and of morphogenesis. In this work, we have studied how intercellular adhesion molecules and β1 integrins influence each other using two different β1-null cell lines, epithelial GE11 and fibroblast-like GD25 cells. Expression of β1A or the cytoplasmic splice variant β1D, induced the disruption of intercellular adherens junctions and cell scattering in both GE11 and GD25 cells. In GE11 cells, the morphological change correlated with the redistribution of zonula occluden (ZO)-1 from tight junctions to adherens junctions at high cell confluency. In addition, the expression of β1 integrins caused a dramatic reorganization of the actin cytoskeleton and of focal contacts. Interaction of β1 integrins with their respective ligands was required for a complete morphological transition towards the spindle-shaped fibroblast-like phenotype. The expression of an interleukin-2 receptor (IL2R)-β1A chimera and its incorporation into focal adhesions also induced the disruption of cadherin-based adhesions and the reorganization of ECM–cell contacts, but failed to promote cell migration on fibronectin, in contrast to full-length β1A. This indicates that the disruption of cell–cell adhesion is not simply the consequence of the stimulated cell migration. Expression of β1 integrins in GE11 cells resulted in a decrease in cadherin and α-catenin protein levels accompanied by their redistribution from the cytoskeleton-associated fraction to the detergent-soluble fraction. Regulation of α-catenin protein levels by β1 integrins is likely to play a role in the morphological transition, since overexpression of α-catenin in GE11 cells before β1 prevented the disruption of intercellular adhesions and cell scattering. In addition, using biochemical activity assays for Rho-like GTPases, we show that the expression of β1A, β1D, or IL2R-β1A in GE11 or GD25 cells triggers activation of both RhoA and Rac1, but not of Cdc42. Moreover, dominant negative Rac1 (N17Rac1) inhibited the disruption of cell–cell adhesions when expressed before β1. However, all three GTPases might be involved in the morphological transition, since expression of either N19RhoA, N17Rac1, or N17Cdc42 reversed cell scattering and partially restored cadherin-based adhesions in GE11-β1A cells. Our results indicate that β1 integrins regulate the polarity and motility of epithelial cells by the induction of intracellular molecular events involving a downregulation of α-catenin function and the activation of the Rho-like G proteins Rac1 and RhoA.

scholarly journals Distinct roles of AKT isoforms in regulating β1-integrin activity, migration, and invasion in prostate cancer

2012 ◽  
Vol 23 (17) ◽  
pp. 3357-3369 ◽  
Author(s):  
Reetta Virtakoivu ◽  
Teijo Pellinen ◽  
Juha K. Rantala ◽  
Merja Perälä ◽  
Johanna Ivaska
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cell Migration ◽  
Tyrosine Kinases ◽  
Migration And Invasion ◽  
Β1 Integrin ◽  
Akt Isoforms ◽  
Feedback Suppression ◽  
Cancer Migration ◽  
Β1 Integrins

AKT1 and AKT2 kinases have been shown to play opposite roles in breast cancer migration and invasion. In this study, an RNA interference screen for integrin activity inhibitors identified AKT1 as an inhibitor of β1-integrin activity in prostate cancer. Validation experiments investigating all three AKT isoforms demonstrated that, unlike in breast cancer, both AKT1 and AKT2 function as negative regulators of cell migration and invasion in PC3 prostate cancer cells. Down-regulation of AKT1 and AKT2, but not AKT3, induced activation of cell surface β1-integrins and enhanced adhesion, migration, and invasion. Silencing of AKT1 and AKT2 also resulted in increased focal adhesion size. Importantly, the mechanisms involved in integrin activity regulation were distinct for the two AKT isoforms. Silencing of AKT1 relieved feedback suppression of the expression and activity of several receptor tyrosine kinases, including EGFR and MET, with established cross-talk with β1-integrins. Silencing of AKT2, on the other hand, induced up-regulation of the microRNA-200 (miR-200) family, and overexpression of miR-200 was sufficient to induce integrin activity and cell migration in PC3 cells. Taken together, these data define an inhibitory role for both AKT1 and AKT2 in prostate cancer migration and invasion and highlight the cell type–specific actions of AKT kinases in the regulation of cell motility.

scholarly journals Rab5 Mediates Caspase-8–promoted Cell Motility and Metastasis

2010 ◽  
Vol 21 (2) ◽  
pp. 369-376 ◽  
Author(s):  
Vicente A. Torres ◽  
Ainhoa Mielgo ◽  
Simone Barbero ◽  
Ruth Hsiao ◽  
John A. Wilkins ◽  
...  
Keyword(s):  
Cell Migration ◽  
Focal Adhesions ◽  
Caspase 8 ◽  
Environmental Cues ◽  
Dependent Manner ◽  
Cell Responses ◽  
Β1 Integrins ◽  
And Migration

Caspase-8 is a key apical sensory protein that governs cell responses to environmental cues, alternatively promoting apoptosis, proliferation, and cell migration. The proteins responsible for integration of these pathways, however, have remained elusive. Here, we reveal that Rab5 regulates caspase-8–dependent signaling from integrins. Integrin ligation leads to Rab5 activation, association with integrins, and activation of Rac, in a caspase-8–dependent manner. Rab5 activation promotes colocalization and coprecipitation of integrins with caspase-8, concomitant with Rab5 recruitment to integrin-rich regions such as focal adhesions and membrane ruffles. Moreover, caspase-8 expression promotes Rab5-mediated internalization and the recycling of β1 integrins, increasing cell migration independently of caspase catalytic activity. Conversely, Rab5 knockdown prevented caspase-8–mediated integrin signaling for Rac activation, cell migration, and apoptotic signaling, respectively. Similarly, Rab5 was critical for caspase-8–driven cell migration in vivo, because knockdown of Rab5 compromised the ability of caspase-8 to promote metastasis under nonapoptotic conditions. These studies identify Rab5 as a key integrator of caspase-8–mediated signal transduction downstream of integrins, regulating cell survival and migration in vivo and in vitro.

scholarly journals Type I Phosphatidylinositol Phosphate Kinase Beta Regulates Focal Adhesion Disassembly by Promoting β1 Integrin Endocytosis

2010 ◽  
Vol 30 (18) ◽  
pp. 4463-4479 ◽  
Author(s):  
Wei-Ting Chao ◽  
Felicity Ashcroft ◽  
Alexes C. Daquinag ◽  
Tegy Vadakkan ◽  
Zhubo Wei ◽  
...  
Keyword(s):  
Cell Migration ◽  
Focal Adhesion ◽  
Focal Adhesions ◽  
Type I ◽  
Adhesion Sites ◽  
Phosphatidylinositol Phosphate ◽  
Β1 Integrins ◽  
Focal Adhesion Turnover ◽  
Dynamin 2 ◽  
Phosphatidylinositol Phosphate Kinase

ABSTRACT Cell migration requires the regulated disassembly of focal adhesions, but the underlying mechanisms remain poorly defined. We have previously shown that focal adhesion disassembly requires the dynamin 2- and clathrin-dependent endocytosis of ligand-activated β1 integrins. Here, we identify type I phosphatidylinositol phosphate kinase beta (PIPKIβ), an enzyme that generates phosphatidylinositol-4,5-bisphosphate (PI4,5P2), as a key regulator of this process. We found that knockdown of PIPKIβ by RNA interference blocks the internalization of active β1 integrins and impairs focal adhesion turnover and cell migration. These defects are caused by the failure to target the endocytic machinery, including clathrin adaptors and dynamin 2, to focal adhesion sites. As a consequence, depletion of PIPKIβ blocks clathrin assembly at adhesion plaques and prevents complex formation between dynamin 2 and focal adhesion kinase (FAK), a critical step in focal adhesion turnover. Together, our findings identify PIPKIβ as a novel regulator of focal adhesion disassembly and suggest that PIPKIβ spatially regulates integrin endocytosis at adhesion sites to control cell migration.

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