scholarly journals Microtubules in cell migration

2019 ◽  
Vol 63 (5) ◽  
pp. 509-520 ◽  
Author(s):  
Clare Garcin ◽  
Anne Straube
Keyword(s):  
Cell Migration ◽  
Cross Talk ◽  
Intracellular Transport ◽  
Rho Gtpase ◽  
Cortical Microtubule ◽  
Focal Adhesions ◽  
Leading Edge ◽  
Long Distance ◽  
Signalling Molecules ◽  
Sequence Of Events

Abstract Directed cell migration is critical for embryogenesis and organ development, wound healing and the immune response. Microtubules are dynamic polymers that control directional migration through a number of coordinated processes: microtubules are the tracks for long-distance intracellular transport, crucial for delivery of new membrane components and signalling molecules to the leading edge of a migrating cell and the recycling of adhesion receptors. Microtubules act as force generators and compressive elements to support sustained cell protrusions. The assembly and disassembly of microtubules is coupled to Rho GTPase signalling, thereby controlling actin polymerisation, myosin-driven contractility and the turnover of cellular adhesions locally. Cross-talk of actin and microtubule dynamics is mediated through a number of common binding proteins and regulators. Furthermore, cortical microtubule capture sites are physically linked to focal adhesions, facilitating the delivery of secretory vesicles and efficient cross-talk. Here we summarise the diverse functions of microtubules during cell migration, aiming to show how they contribute to the spatially and temporally coordinated sequence of events that permit efficient, directional and persistent migration.

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.

Engineering Tools for Studying Coordination Between Biochemical and Biomechanical Activities in Cell Migration

2011 ◽  
Author(s):  
Sungsoo Na
Keyword(s):  
Cell Migration ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Resonance Energy Transfer ◽  
Focal Adhesions ◽  
Resonance Energy ◽  
Leading Edge ◽  
Dynamic Feedback ◽  
Chemical Signaling ◽  
Directed Cell Migration

Cell migration is achieved by the dynamic feedback interactions between traction forces generated by the cell and exerted onto the underlying extracellular matrix (ECM), and intracellular mechano-chemical signaling pathways, e.g., Rho GTPase (RhoA, Rac1, and Cdc42) activities [1,2,3]. These components are differentially distributed within a cell, and thus the coordination between tractions and mechanotransduction (i.e, RhoA and Rac1 activities) must be implemented at a precise spatial and temporal order to achieve optimized, directed cell migration [4,5]. Recent studies have shown that focal adhesions at the leading edge exert strong tractions [6], and these traction sites are co-localized with focal adhesion sites [7]. Further, by using the fluorescence resonance energy transfer (FRET) technology coupled with genetically encoded biosensors, researchers reported that Rho GTPases, such as RhoA [8], Rac1 [9], and Cdc42 [10] are maximally activated at the leading edge, suggesting the leading edge of the cell as its common functional site for Rho GTPase activities. All these works, however, were done separately, and the relationship between tractions and mechanotransduction during cell migration has not been demonstrated directly because of the difficulty in simultaneously recording tractions and mechanotransduction in migrating cells, precluding direct comparison between these results. Furthermore, these studies have been conducted by monitoring cells on glass coverslips, the stiffness of which is ∼ 65 giga pascal (GPa), at least three to six order higher than the physiological range of ECM stiffness. Although it is increasingly accepted that ECM stiffness influences cell migration, it is not known exactly how physiologically relevant ECM stiffness (order of kPa range) affects the dynamics of RhoA and Rac1 activities. For a complete understanding of the mechanism of mechano-chemical signaling in the context of cell migration, the dynamics and interplay between biomechanical (e.g., tractions) and biochemical (e.g., Rho GTPase) activities should be visualized within the physiologically relevant range of ECM stiffness.

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 Essential and nonredundant roles for Diaphanous formins in cortical microtubule capture and directed cell migration

2014 ◽  
Vol 25 (5) ◽  
pp. 658-668 ◽  
Author(s):  
Pascale Daou ◽  
Salma Hasan ◽  
Dennis Breitsprecher ◽  
Emilie Baudelet ◽  
Luc Camoin ◽  
...  
Keyword(s):  
Cell Migration ◽  
Actin Polymerization ◽  
Affinity Purification ◽  
Cortical Microtubule ◽  
Leading Edge ◽  
Large Family ◽  
Mass Spectrometry Analysis ◽  
Cell Cortex ◽  
Spectrometry Analysis ◽  
Microtubule Capture

Formins constitute a large family of proteins that regulate the dynamics and organization of both the actin and microtubule cytoskeletons. Previously we showed that the formin mDia1 helps tether microtubules at the cell cortex, acting downstream of the ErbB2 receptor tyrosine kinase. Here we further study the contributions of mDia1 and its two most closely related formins, mDia2 and mDia3, to cortical microtubule capture and ErbB2-dependent breast carcinoma cell migration. We find that depletion of each of these three formins strongly disrupts chemotaxis without significantly affecting actin-based structures. Further, all three formins are required for formation of cortical microtubules in a nonredundant manner, and formin proteins defective in actin polymerization remain active for microtubule capture. Using affinity purification and mass spectrometry analysis, we identify differential binding partners of the formin-homology domain 2 (FH2) of mDia1, mDia2, and mDia3, which may explain their nonredundant roles in microtubule capture. The FH2 domain of mDia1 specifically interacts with Rab6-interacting protein 2 (Rab6IP2). Further, mDia1 is required for cortical localization of Rab6IP2, and concomitant depletion of Rab6IP2 and IQGAP1 severely disrupts cortical capture of microtubules, demonstrating the coinvolvement of mDia1, IQGAP1, and Rab6IP2 in microtubule tethering at the leading edge.

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 Targeting and transport: How microtubules control focal adhesion dynamics

2012 ◽  
Vol 198 (4) ◽  
pp. 481-489 ◽  
Author(s):  
Samantha Stehbens ◽  
Torsten Wittmann
Keyword(s):  
Extracellular Matrix ◽  
Cell Migration ◽  
Focal Adhesion ◽  
Molecular Mechanisms ◽  
Rho Gtpase ◽  
Focal Adhesions ◽  
Matrix Metalloproteases ◽  
Force Generation ◽  
Diverse Group ◽  
Directional Cell Migration

Directional cell migration requires force generation that relies on the coordinated remodeling of interactions with the extracellular matrix (ECM), which is mediated by integrin-based focal adhesions (FAs). Normal FA turnover requires dynamic microtubules, and three members of the diverse group of microtubule plus-end-tracking proteins are principally involved in mediating microtubule interactions with FAs. Microtubules also alter the assembly state of FAs by modulating Rho GTPase signaling, and recent evidence suggests that microtubule-mediated clathrin-dependent and -independent endocytosis regulates FA dynamics. In addition, FA-associated microtubules may provide a polarized microtubule track for localized secretion of matrix metalloproteases (MMPs). Thus, different aspects of the molecular mechanisms by which microtubules control FA turnover in migrating cells are beginning to emerge.

scholarly journals Local Myo9b RhoGAP activity regulates cell motility

2020 ◽  
pp. jbc.RA120.013623
Author(s):  
Sandra Angela Hemkemeyer ◽  
Veith Vollmer ◽  
Vera Schwarz ◽  
Birgit Lohmann ◽  
Ulrike Honnert ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Cell Morphology ◽  
Actin Polymerization ◽  
Rho Gtpase ◽  
Leading Edge ◽  
Cell Extension ◽  
Local Inhibition ◽  
And Migration ◽  
Directional Cell Migration

To migrate, cells assume a polarized morphology, extending forward with a leading edge with their trailing edge retracting back toward the cell body. Both cell extension and retraction critically depend on the organization and dynamics of the actin cytoskeleton, and the small, monomeric GTPases Rac and Rho are important regulators of actin. Activation of Rac induces actin polymerization and cell extension whereas activation of Rho enhances acto-myosin II contractility and cell retraction. To coordinate migration, these processes must be carefully regulated. The myosin Myo9b, a Rho GTPase activating protein (GAP), negatively regulates Rho activity and deletion of Myo9b in leukocytes impairs cell migration through increased Rho activity. However, it is not known whether cell motility is regulated by global or local inhibition of Rho activity by Myo9b. Here, we addressed this question by using Myo9b-deficient macrophage-like cells that expressed different recombinant Myo9b constructs. We found that Myo9b accumulates in lamellipodial extensions generated by Rac-induced actin polymerization as a function of its motor activity. Deletion of Myo9b in HL-60 derived macrophages altered cell morphology and impaired cell migration. Reintroduction of Myo9b or Myo9b motor and GAP mutants revealed that local GAP activity rescues cell morphology and migration. In summary, Rac activation leads to actin polymerization and recruitment of Myo9b, which locally inhibits Rho activity to enhance directional cell migration. In summary, Rac activation leads to actin polymerization and recruitment of Myo9b, which locally inhibits Rho activity to enhance directional cell migration.

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