scholarly journals Membrane dynamics in cell migration

2019 ◽  
Vol 63 (5) ◽  
pp. 469-482 ◽  
Author(s):  
Montserrat Llanses Martinez ◽  
Elena Rainero
Keyword(s):  
Cell Migration ◽  
Cancer Metastasis ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Tissue Level ◽  
Membrane Dynamics ◽  
Surface Receptors ◽  
Extracellular Molecules ◽  
Migratory Cells ◽  
Endocytic Proteins

Abstract Migration of cells is required in multiple tissue-level processes, such as in inflammation or cancer metastasis. Endocytosis is an extremely regulated cellular process by which cells uptake extracellular molecules or internalise cell surface receptors. While the role of endocytosis of focal adhesions (FA) and plasma membrane (PM) turnover at the leading edge of migratory cells is wide known, the contribution of endocytic proteins per se in migration has been frequently disregarded. In this review, we describe the novel functions of the most well-known endocytic proteins in cancer cell migration, focusing on clathrin, caveolin, flotillins and GRAF1. In addition, we highlight the relevance of the macropinocytic pathway in amoeboid-like cell migration.

scholarly journals R-Ras Controls Membrane Protrusion and Cell Migration through the Spatial Regulation of Rac and Rho

2005 ◽  
Vol 16 (1) ◽  
pp. 84-96 ◽  
Author(s):  
Michele A. Wozniak ◽  
Lina Kwong ◽  
David Chodniewicz ◽  
Richard L. Klemke ◽  
Patricia J. Keely
Keyword(s):  
Cell Migration ◽  
Molecular Mechanisms ◽  
Leading Edge ◽  
Pi3 Kinase ◽  
Dominant Negative ◽  
Cell Periphery ◽  
Membrane Protrusion ◽  
Spatial Regulation ◽  
Entire Cell ◽  
Migratory Cells

Although it is known that the spatial coordination of Rac and Rho activity is essential for cell migration, the molecular mechanisms regulating these GTPases during migration are unknown. We found that the expression of constitutively activated R-Ras (38V) blocked membrane protrusion and random migration. In contrast, expression of dominant negative R-Ras (41A) enhanced migrational persistence and membrane protrusion. Endogenous R-Ras is necessary for cell migration, as cells that were transfected with siRNA for R-Ras did not migrate. Expression of R-Ras (38V) decreased Rac activity and increased Rho activity around the entire cell periphery, whereas expression of dominant negative R-Ras (41A) showed the converse, suggesting that R-Ras can spatially activate Rho and inactivate Rac. Consistent with this role, endogenous R-Ras localized and was preferentially activated at the leading edge of migratory cells in response to adhesion. The effects of R-Ras on cell migration are mediated by PI3-Kinase, as an effector mutant that uncouples PI3-Kinase binding from R-Ras (38V) rescued migration. From these data, we hypothesize that R-Ras plays a key role in cell migration by locally regulating the switch from Rac to Rho activity after membrane protrusion and adhesion.

scholarly journals Rab40/Cullin5 complex regulates EPLIN and actin cytoskeleton dynamics during cell migration and invasion

2021 ◽  
Author(s):  
Erik S Linklater ◽  
Emily Duncan ◽  
Ke Jun Han ◽  
Algirdas Kaupinis ◽  
Mindaugas Valius ◽  
...  
Keyword(s):  
Cell Migration ◽  
Actin Cytoskeleton ◽  
Focal Adhesion ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Stress Fibers ◽  
Actin Dynamics ◽  
Migration And Invasion ◽  
Matrix Remodeling ◽  
Cell Migration And Invasion

Rab40b is a SOCS box containing protein that regulates the secretion of MMPs to facilitate extracellular matrix remodeling during cell migration. Here we show that Rab40b interacts with Cullin5 via the Rab40b SOCS domain. We demonstrate that loss of Rab40b/Cullin5 binding decreases cell motility and invasive potential, and show that defective cell migration and invasion stem from alteration to the actin cytoskeleton, leading to decreased invadopodia formation, decreased actin dynamics at the leading edge, and an increase in stress fibers. We also show that these stress fibers anchor at less dynamic, more stable focal adhesions. Mechanistically, changes in the cytoskeleton and focal adhesion dynamics are mediated in part by EPLIN, which we demonstrate to be a binding partner of Rab40b and a target for Rab40b/Cullin5 dependent localized ubiquitylation and degradation. Thus, we propose a model where the Rab40b/Cullin5 dependent ubiquitylation regulates EPLIN localization to promote cell migration and invasion by altering focal adhesion and cytoskeletal dynamics.

scholarly journals Cell migration: Fibroblasts find a new way to get ahead

2012 ◽  
Vol 197 (3) ◽  
pp. 347-349 ◽  
Author(s):  
Michael Sixt
Keyword(s):  
Cell Migration ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Two Dimensional ◽  
Tissue Explants ◽  
Cell Biol ◽  
Membrane Blebs ◽  
3D Environments ◽  
Actomyosin Contraction ◽  
Phosphatidylinositol 3

Fibroblasts migrate on two-dimensional (2D) surfaces by forming lamellipodia—actin-rich extensions at the leading edge of the cell that have been well characterized. In this issue, Petrie et al. (2012. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201201124) show that in some 3D environments, including tissue explants, fibroblasts project different structures, termed lobopodia, at the leading edge. Lobopodia still assemble focal adhesions; however, similar to membrane blebs, they are driven by actomyosin contraction and do not accumulate active Rac, Cdc42, and phosphatidylinositol 3-kinases.

scholarly journals Interaction of monocarboxylate transporter 4 with β1-integrin and its role in cell migration

2009 ◽  
Vol 296 (3) ◽  
pp. C414-C421 ◽  
Author(s):  
Shannon M. Gallagher ◽  
John J. Castorino ◽  
Nancy J. Philp
Keyword(s):  
Cell Migration ◽  
Focal Adhesion ◽  
Mdck Cells ◽  
Basolateral Membrane ◽  
Specific Interaction ◽  
Cell Movement ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Monocarboxylate Transporter ◽  
Epithelial Cell Lines

Monocarboxylate transporter (MCT) 4 is a heteromeric proton-coupled lactate transporter that is noncovalently linked to the extracellular matrix metalloproteinase inducer CD147 and is typically expressed in glycolytic tissues. There is increasing evidence to suggest that ion transporters are part of macromolecular complexes involved in regulating β1-integrin adhesion and cell movement. In the present study we examined whether MCTs play a role in cell migration through their interaction with β1-integrin. Using reciprocal coimmunoprecipitation assays, we found that β1-integrin selectively associated with MCT4 in ARPE-19 and MDCK cells, two epithelial cell lines that express both MCT1 and MCT4. In polarized monolayers of ARPE-19 cells, MCT4 and β1-integrin colocalized to the basolateral membrane, while both proteins were found in the leading edge lamellapodia of migrating cells. In scratch-wound assays, MCT4 knockdown slowed migration and increased focal adhesion size. In contrast, silencing MCT1 did not alter the rate of cell migration or focal adhesion size. Taken together, our findings suggest that the specific interaction of MCT4 with β1-integrin may regulate cell migration through modulation of focal adhesions.

scholarly journals α4/α9 Integrins Coordinate Epithelial Cell Migration Through Local Suppression of MAP Kinase Signaling Pathways

2021 ◽  
Vol 9 ◽  
Author(s):  
Willow Hight-Warburton ◽  
Robert Felix ◽  
Andrew Burton ◽  
Hannah Maple ◽  
Magda S. Chegkazi ◽  
...  
Keyword(s):  
Cell Migration ◽  
Protein Complexes ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Collective Cell Migration ◽  
Keratinocyte Proliferation ◽  
Basal Keratinocytes ◽  
Keratinocyte Cell

Adhesion of basal keratinocytes to the underlying extracellular matrix (ECM) plays a key role in the control of skin homeostasis and response to injury. Integrin receptors indirectly link the ECM to the cell cytoskeleton through large protein complexes called focal adhesions (FA). FA also function as intracellular biochemical signaling platforms to enable cells to respond to changing extracellular cues. The α4β1 and α9β1 integrins are both expressed in basal keratinocytes, share some common ECM ligands, and have been shown to promote wound healing in vitro and in vivo. However, their roles in maintaining epidermal homeostasis and relative contributions to pathological processes in the skin remain unclear. We found that α4β1 and α9β1 occupied distinct regions in monolayers of a basal keratinocyte cell line (NEB-1). During collective cell migration (CCM), α4 and α9 integrins co-localized along the leading edge. Pharmacological inhibition of α4β1 and α9β1 integrins increased keratinocyte proliferation and induced a dramatic change in cytoskeletal remodeling and FA rearrangement, detrimentally affecting CCM. Further analysis revealed that α4β1/α9β1 integrins suppress extracellular signal-regulated kinase (ERK1/2) activity to control migration through the regulation of downstream kinases including Mitogen and Stress Activated Kinase 1 (MSK1). This work demonstrates the roles of α4β1 and α9β1 in regulating migration in response to damage cues.

scholarly journals Mechanochemical coupling and junctional forces during collective cell migration

2019 ◽  
Author(s):  
J. Bui ◽  
D. E. Conway ◽  
R. L. Heise ◽  
S.H. Weinberg
Keyword(s):  
Cell Migration ◽  
Rho Gtpases ◽  
Cancer Metastasis ◽  
Rho Gtpase ◽  
Critical Role ◽  
Leading Edge ◽  
Collective Cell Migration ◽  
Gtpase Activity ◽  
Modeling Framework ◽  
Cell Cell

ABSTRACTCell migration, a fundamental physiological process in which cells sense and move through their surrounding physical environment, plays a critical role in development and tissue formation, as well as pathological processes, such as cancer metastasis and wound healing. During cell migration, dynamics are governed by the bidirectional interplay between cell-generated mechanical forces and the activity of Rho GTPases, a family of small GTP-binding proteins that regulate actin cytoskeleton assembly and cellular contractility. These interactions are inherently more complex during the collective migration of mechanically coupled cells, due to the additional regulation of cell-cell junctional forces. In this study, we present a minimal modeling framework to simulate the interactions between mechanochemical signaling in individual cells and interactions with cell-cell junctional forces during collective cell migration. We find that migration of individual cells depends on the feedback between mechanical tension and Rho GTPase activity in a biphasic manner. During collective cell migration, waves of Rho GTPase activity mediate mechanical contraction/extension and thus synchronization throughout the tissue. Further, cell-cell junctional forces exhibit distinct spatial patterns during collective cell migration, with larger forces near the leading edge. Larger junctional force magnitudes are associated with faster collective cell migration and larger tissue size. Simulations of heterogeneous tissue migration exhibit a complex dependence on the properties of both leading and trailing cells. Computational predictions demonstrate that collective cell migration depends on both the emergent dynamics and interactions between cellular-level Rho GTPase activity and contractility, and multicellular-level junctional forces.

scholarly journals Cortical dynamics during cell motility are regulated by CRL3KLHL21 E3 ubiquitin ligase

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Thibault Courtheoux ◽  
Radoslav I. Enchev ◽  
Fabienne Lampert ◽  
Juan Gerez ◽  
Jochen Beck ◽  
...  
Keyword(s):  
Cell Migration ◽  
Ubiquitin Ligase ◽  
Cortical Plasticity ◽  
Cortical Microtubule ◽  
E3 Ubiquitin Ligase ◽  
Cell Movement ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Cell Cortex ◽  
Cortical Dynamics

Abstract Directed cell movement involves spatial and temporal regulation of the cortical microtubule (Mt) and actin networks to allow focal adhesions (FAs) to assemble at the cell front and disassemble at the rear. Mts are known to associate with FAs, but the mechanisms coordinating their dynamic interactions remain unknown. Here we show that the CRL3KLHL21 E3 ubiquitin ligase promotes cell migration by controlling Mt and FA dynamics at the cell cortex. Indeed, KLHL21 localizes to FA structures preferentially at the leading edge, and in complex with Cul3, ubiquitylates EB1 within its microtubule-interacting CH-domain. Cells lacking CRL3KLHL21 activity or expressing a non-ubiquitylatable EB1 mutant protein are unable to migrate and exhibit strong defects in FA dynamics, lamellipodia formation and cortical plasticity. Our study thus reveals an important mechanism to regulate cortical dynamics during cell migration that involves ubiquitylation of EB1 at focal adhesions.

scholarly journals STIM1 Controls the Focal Adhesion Dynamics and Cell Migration by Regulating SOCE in Osteosarcoma

2021 ◽  
Vol 23 (1) ◽  
pp. 162
Author(s):  
Yu-Shan Lin ◽  
Yi-Hsin Lin ◽  
MyHang Nguyen Thi ◽  
Shih-Chuan Hsiao ◽  
Wen-Tai Chiu
Keyword(s):  
Cell Migration ◽  
Focal Adhesion ◽  
Cancer Metastasis ◽  
Focal Adhesions ◽  
Dominant Negative ◽  
Osteosarcoma Cell ◽  
Wild Type ◽  
Calpain Activity ◽  
The Impact ◽  
Constitutively Active

The dysregulation of store-operated Ca2+ entry (SOCE) promotes cancer progression by changing Ca2+ levels in the cytosol or endoplasmic reticulum. Stromal interaction molecule 1 (STIM1), a component of SOCE, is upregulated in several types of cancer and responsible for cancer cell migration, invasion, and metastasis. To explore the impact of STIM1-mediated SOCE on the turnover of focal adhesion (FA) and cell migration, we overexpressed the wild-type and constitutively active or dominant negative variants of STIM1 in an osteosarcoma cell line. In this study, we hypothesized that STIM1-mediated Ca2+ elevation may increase cell migration. We found that constitutively active STIM1 dramatically increased the Ca2+ influx, calpain activity, and turnover of FA proteins, such as the focal adhesion kinase (FAK), paxillin, and vinculin, which impede the cell migration ability. In contrast, dominant negative STIM1 decreased the turnover of FA proteins as its wild-type variant compared to the cells without STIM1 overexpression while promoting cell migration. These unexpected results suggest that cancer cells need an appropriate amount of Ca2+ to control the assembly and disassembly of focal adhesions by regulating calpain activity. On the other hand, overloaded Ca2+ results in excessive calpain activity, which is not beneficial for cancer metastasis.

scholarly journals A Role for P21-Activated Kinase in Endothelial Cell Migration

1999 ◽  
Vol 147 (4) ◽  
pp. 831-844 ◽  
Author(s):  
William B. Kiosses ◽  
R. Hugh Daniels ◽  
Carol Otey ◽  
Gary M. Bokoch ◽  
Martin Alexander Schwartz
Keyword(s):  
Cell Migration ◽  
Fluorescent Protein ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Dominant Negative ◽  
Endothelial Cell Migration ◽  
Stress Fibers ◽  
Membrane Ruffling ◽  
Cell Contractility ◽  
P21 Activated Kinase

The serine/threonine p21-activated kinase (PAK) is an effector for Rac and Cdc42, but its role in regulating cytoskeletal organization has been controversial. To address this issue, we investigated the role of PAK in migration of microvascular endothelial cells. We found that a dominant negative (DN) mutant of PAK significantly inhibited cell migration and in-creased stress fibers and focal adhesions. The DN effect mapped to the most NH2-terminal proline-rich SH3-binding sequence. Observation of a green fluorescent protein-tagged α-actinin construct in living cells revealed that the DN construct had no effect on membrane ruffling, but dramatically inhibited stress fiber and focal contact motility and turnover. Constitutively active PAK inhibited migration equally well and also increased stress fibers and focal adhesions, but had a somewhat weaker effect on their dynamics. In contrast to their similar effects on motility, DN PAK decreased cell contractility, whereas active PAK increased contractility. Active PAK also increased myosin light chain (MLC) phosphorylation, as indicated by staining with an antibody to phosphorylated MLC, whereas DN PAK had little effect, despite the increase in actin stress fibers. These results demonstrate that although PAK is not required for extension of lamellipodia, it has substantial effects on cell adhesion and contraction. These data suggest a model in which PAK plays a role coordinating the formation of new adhesions at the leading edge with contraction and detachment at the trailing edge.

Vascular Endothelial Growth Factor (VEGF)-Induced Endothelial Cell Migration Requires Urokinase Receptor (uPAR) for Integrin Redistribution.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 846-846
Author(s):  
Gerald W. Prager ◽  
Johannes M. Breuss4 ◽  
Patrick Brunner4 ◽  
Bernd R. Binder4
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Focal Adhesions ◽  
Specific Inhibitor ◽  
Leading Edge ◽  
Urokinase Receptor ◽  
Endothelial Cell Migration ◽  
Spatial Proximity

Abstract VEGF activates endothelial cells to migrate and invade surrounding tissues, an initial event in the angiogenic process. For invasion, the coordinated localized formation of a proteolytic repertoir is necessary. Focusing the urokinase receptor towards the leading edge of migrating cells provides such armor and inhibition of uPA binding to its receptor inhibits invasion of endothelial cells. In addition integrins continuously have to form focal contacts at the leading edge. Thus the spatial proximity between the localized proteases and the matrix seems to be essential for matrix degradation. In order to allow cell locomotion integrins have to release their ligands when they reach the trailing end and are subsequently endocytosed and redistributed to newly formed focal adhesions in a repetitive process. We here describe a new role of uPAR in regulating integrin redistribution. We have previously reported that stimulation of human endothelial cells by VEGF (50ng/ml) via its receptor flk-1 induces pro-uPA activation, when bound to uPAR. Subsequently a uPA/PAI-1/uPAR-complex is formed, which thereafter is endocytosed via a LDL-R family member. We now show that by this process beta-1 integrins are co-internalized in clathrin coated vesicles via a uPAR dependent mechanism. Subsequently, endocytosed uPAR recycles to focal adhesions where it co-localizes with integrin alpha-v/beta-3. Disrupting this chain of events, either by (1) RAP - a specific inhibitor of the LDL-R family - or by (2) uPAR depletion (using uPAR−/− cells or cleaving the GPI-anchor of uPAR by PI-PLC), beta-1 integrins are no longer internalized after VEGF stimulation. Under the same circumstances the migratory response of endothelial cells toward VEGF is impaired in vitro as shown by video-based migration assays and in vivo as demonstrated by matrigel angiogenesis assays. Next, we generated synthetic peptides interfering with uPAR/integrin interaction, which inhibit not only VEGF-induced integrin redistribution, but also diminish VEGF-induced endothelial cell migration, significantly. These data suggest that in VEGF-induced cell migration uPAR plays a central role not only in focusing proteolytic activity, but also in initial integrin redistribution. Interference with this process could be a therapeutic target for diseases depending on VEGF-induced angiogenesis.

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