Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound . Cell migration is a broad term that we use to refer to those processes that involve the translation of cells from one location to another. This may occur in non-live. Cell migration is a fundamental process, from simple, uni-cellular organisms such as amoeba, to complex multi-cellular organisms such as mammals. Whereas.
It generally involves drastic changes in cell shape which are driven by the cytoskeleton. Two very distinct migration scenarios are crawling motion most commonly studied and blebbing motility.
The migration of cultured cells attached to a surface is commonly studied using microscopy. Such videos Figure 1 reveal that the leading cell front is very active, with a characteristic behavior of successive contractions and expansions. It is generally accepted that the leading front is the main motor that pulls the cell forward.
The processes underlying mammalian cell migration are believed to be consistent with those of non- spermatozooic locomotion. The latter feature is most easily observed when aggregates of a surface molecule are cross-linked with a fluorescent antibody or when small beads become artificially bound to the front of the cell.
Other eukaryotic cells are observed to migrate similarly. The amoeba Dictyostelium discoideum is useful to researchers because they consistently exhibit chemotaxis in response to cyclic AMP ; they move more quickly than cultured mammalian cells; and they have a haploid genome that simplifies the process of connecting a particular gene product with its effect on cellular behaviour.
There are two main theories for how the cell advances its front edge: It is possible that both underlying processes contribute to cell extension. Experimentation has shown that there is rapid actin polymerisation at the cell's front edge. Other cytoskeletal components like microtubules have important functions in cell migration. When microtubules in the trailing edge of cell are dynamic, they are able to remodel to allow retraction.
When dynamics are suppressed, microtubules cannot remodel and, therefore, oppose the contractile forces. It can be concluded that microtubules act both to restrain cell movement and to establish directionality. Studies have also shown that the front of the migration is the site at which the membrane is returned to the cell surface from internal membrane pools at the end of the endocytic cycle.
If so, the actin filaments that form at the front might stabilize the added membrane so that a structured extension, or lamella, is formed rather than a bubble-like structure or bleb at its front.
It is likely that these feet are endocytosed toward the rear of the cell and brought to the cell's front by exocytosis, to be reused to form new attachments to the substrate. Based on some mathematical models, recent studies hypothesize a novel biological model for collective biomechanical and molecular mechanism of cell motion. According to this model, microdomain signaling dynamics organizes cytoskeleton and its interaction with substratum.
As microdomains trigger and maintain active polymerization of actin filaments, their propagation and zigzagging motion on the membrane generate a highly interlinked network of curved or linear filaments oriented at a wide spectrum of angles to the cell boundary.
It is also proposed that microdomain interaction marks the formation of new focal adhesion sites at the cell periphery. Finally, continuous application of stress on the old focal adhesion sites could result in the calcium-induced calpain activation, and consequently the detachment of focal adhesions which completes the cycle. Migrating cells have a polarity —a front and a back.
Without it, they would move in all directions at once, i. How this polarity is formulated at a molecular level inside a cell is unknown. In a cell that is meandering in a random way, the front can easily give way to become passive as some other region, or regions, of the cell form s a new front. In chemotaxing cells, the stability of the front appears enhanced as the cell advances toward a higher concentration of the stimulating chemical.
This polarity is reflected at a molecular level by a restriction of certain molecules to particular regions of the inner cell surface. Drugs that destroy actin filaments have multiple and complex effects, reflecting the wide role that these filaments play in many cell processes.
In chemotaxing cells, the increased persistence of migration toward the target may result from an increased stability of the arrangement of the filamentous structures inside the cell and determine its polarity. In turn, these filamentous structures may be arranged inside the cell according to how molecules like PIP3 and PTEN are arranged on the inner cell membrane.
Although microtubules have been known to influence cell migration for many years, the mechanism by which they do so has remained controversial. On a planar surface, microtubules are not needed for the movement, but they are required to provide directionality to cell movement and efficient protrusion of the leading edge.
In a series of recent works, a new area of research called inverse problems in cell motility has been established. Reading cell motion, namely, understanding the underlying biophysical and mechanochemical processes, is of paramount importance. Because excitation is local, whereas the inhibitor is more global, in a gradient there is a persistent deflection of the response regulator above and below its basal level at the front and back of the cell, respectively.
Responses to uniform increases and gradients of chemoattractants in a LEGI model. PIP 3 levels rise transiently during persistent stimulation with a uniform chemoattractant. A LEGI model assumes that the level of a response regulator is controlled by the difference between rapid excitatory and slower inhibitory processes. The response regulator RR, blue line rises when excitation green line is higher than inhibition red line and then falls as inhibition catches up.
B The micrograph shows that the steady-state accumulation of PIP 3 forms a crescent facing the high side of the gradient produced by a micropipette releasing chemoattractant. In the LEGI model, the response regulator blue line rises when excitation green line is higher than inhibition red line and then falls to a new steady state. Because inhibition is more global than the excitation the differences generate a response regulator that has a higher concentration than basal at the front and a lower concentration than basal at the back.
The LEGI model is a useful conceptual device that allows one to predict the response to any combination of applied temporal and spatial stimuli, but further studies are needed to define the underlying biochemical events and to link the model to cell migration.
First, the excitatory process likely corresponds to G-protein activation. When cells are exposed to chemoattractant, the G-protein subunits dissociate within a few seconds and all of the biochemical responses in the network are triggered.
During the next several minutes, the responses gradually subside even though the G protein does not reassociate. The mechanism that offsets the activity of the G-protein and causes the responses to subside remains to be determined.
Second, LEGI schemes can account for all of the behavior of immobilized cells but fail to explain migration or polarity. However, the output of LEGI could enhance excitability at the front and suppress it at the rear Xiong et al. This would ensure that the system responds to the steepness of a gradient but is independent of its midpoint concentration. LEGI-BEN schemes are capable of extraordinary sensitivity, and computer simulations show that this model can produce realistic temporal and spatial chemotactic responses.
Many of the principles described in this article appear to be general and apply to cellular behaviors analogous to migration. For example, dendritic spines, small extensions along dendrites of neurons in the central nervous system, contain a highly organized postsynaptic density that receives excitatory signals. Like protrusions in migrating cells, dendritic spines are highly dynamic, they undergo complex morphologic changes, and they contain a highly organized adhesion associated with the postsynaptic density.
Actin polymerization and actomyosin activity play a major role in spine and postsynaptic density PSD organization Oertner and Matus ; Hodges et al. Rho-family GTPases have emerged as major regulators of spine organization and dynamics and are implicated in human cognitive diseases.
Indeed, mutations in regulators of Rho-family GTPases are implicated in spine-related diseases including autism, schizophrenia, and nonsyndromic mental retardation. Asymmetric localization of PIP 3 is observed in many migrating cells. Oncogenic mutations leading to overproduction of PIP 3 are typically assumed to increase growth rates; but it is likely that many of the cancer-causing effects can also be attributed to alterations in the cytoskeleton Kim et al.
Distortion of cell migration signaling networks plays a critical role in migration-related diseases such as invasive and metastatic cancer Sever and Brugge The plethora of signaling pathways that converge on Rho GTPases means there is a very large potential set of loci for the misregulation of migration.
It also suggests that drugs directed against any particular pathway may not be effective for long given the selection that occurs in the tumor environment. However, the convergence on Rho-family GTPases and the limited migration machinery on which it acts hold promise for therapeutic strategies targeting these GTPases and their downstream effectors or diagnostic routes to identifying cells with invasive potential.
Another emerging area of research is the study of migration in 3D. Until recently, most migration studies focused on migration on planar substrates using integrin-mediated adhesion. Analogous mechanisms are probably used by cells migrating in 3D, or using other receptors e. However, different pathways might play more prominent roles in each case. For example, in 3D, cell protrusions, adhesion, and cell morphology all appear to differ from that generally seen on rigid planar 2D substrates Even-Ram and Yamada ; Provenzano et al.
In 3D, the cells are more elongated and possess narrower protrusions and smaller adhesions Harunaga and Yamada Moreover, there is evidence that different signaling pathways are indeed involved.
For example, depleting paxillin produces a mesenchymal phenotype in 3D environments, whereas depleting the paxillin relative Hic5 produces an amoeboid morphology Deakin and Turner , The particular signaling pathway used seems to depend on the cellular microenvironment, which can differ between normal and tumor cells.
Research into cell migration has clearly made enormous progress. The basic machines that drive migration have been described, and many of the pathways that regulate them have been identified. However, we have only scratched the surface and much remains to be understood. The interactions and regulation of the complex signaling networks that orchestrate migration and the mechanism by which extracellular forces affect these networks are not understood.
Furthermore, new modes of migration are being uncovered, including blebbing-mediated migration and the newly described lobopodia migration Petrie et al. In addition, migration in complex in vivo environments differs from that seen on rigid planar substrates and its study presents unexpected challenges. Finally, integrative, quantitative models of migration that conjoin the plethora of regulatory networks are only now beginning to be developed.
Additional Perspectives on Signal Transduction available at www. Previous Section Next Section. Comparative dynamics of retrograde actin flow and focal adhesions: Formation of nascent adhesions triggers transition from fast to slow flow.
CrossRef Medline Google Scholar. Self-organization of the phosphatidylinositol lipids signaling system for random cell migration. Proc Natl Acad Sci Towards resolving a pointed controversy at the barbed end.
J Cell Sci Annu Rev Cell Dev Biol Chemoattractant signaling and leukocyte activation. Biology of the pactivated kinases. Annu Rev Biochem The three-dimensional dynamics of actin waves, a model of cytoskeletal self-organization. Asymmetric focal adhesion disassembly in motile cells.
Curr Opin Cell Biol Probing the integrin-actin linkage using high-resolution protein velocity mapping. Control of actin filament treadmilling in cell motility. Annu Rev Biophys J Cell Biol A novel integrin-mediated adhesion complex coupled to ventral actin polymerization. Regulation of adhesion dynamics by calpain-mediated proteolysis of focal adhesion kinase FAK. J Biol Chem Blebs lead the way: How to migrate without lamellipodia. Nat Rev Mol Cell Biol 9: A novel cytosolic regulator, Pianissimo, is required for chemoattractant receptor and G protein-mediated activation of the twelve transmembrane domain adenylyl cyclase in Dictyostelium.
Two phases of actin polymerization display different dependences on PI 3,4,5 P 3 accumulation and have unique roles during chemotaxis. Mol Biol Cell The integrin-ligand interaction regulates adhesion and migration through a molecular clutch. Unleashing formins to remodel the actin and microtubule cytoskeletons.
Nat Rev Mol Cell Biol Nat Cell Biol Cross-correlated fluctuation analysis reveals phosphorylation-regulated paxillin-FAK complexes in nascent adhesions. Mechanically induced actin-mediated rocketing of phagosomes. A conformational switch in vinculin drives formation and dynamics of a talin-vinculin complex at focal adhesions.
Phosphoinositides specify polarity during epithelial organ development. Condeelis J Condeelis J. How is actin polymerization nucleated in vivo? Trends Cell Biol Calpain-mediated proteolysis of paxillin negatively regulates focal adhesion dynamics and cell migration.
Paxillin comes of age. Distinct roles for paxillin and Hic-5 in regulating breast cancer cell morphology, invasion, and metastasis. Stretching single talin rod molecules activates vinculin binding. Central regulatory molecules in Rho GTPase activation. Distinctions between directional sensing and polarization.
Chemotaxis in eucaryotic cells: A focus on leukocytes and Dictyostelium. Ann Rev Cell Biol 4: Lateral membrane waves constitute a universal dynamic pattern of motile cells. Phys Rev Lett Signaling pathways controlling primordial germ cell migration in zebrafish. Cdc42—The centre of polarity.
Rho GTPases in cell biology. Par6, aPKC and cytoskeletal crosstalk. Cell migration in 3D matrix. Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase.
Nat Cell Biol 7: Clathrin mediates integrin endocytosis for focal adhesion disassembly in migrating cells. Cell motility through plasma membrane blebbing. Nat Cell Biol 9: Organizing the structure and function of FAK. Calpain-mediated proteolysis of talin regulates adhesion dynamics. Nat Cell Biol 6: Cancer invasion and the microenvironment: Collective cell migration in morphogenesis, regeneration and cancer. Plasticity of cell migration: A multiscale tuning model.
Molecular architecture and function of matrix adhesions. Cold Spring Harb Perspect Biol 3: Cytoskeletal dynamics in growth-cone steering. Gerisch G Gerisch G. Self-organizing actin waves that simulate phagocytic cup structures. Mobile actin clusters and traveling waves in cells recovering from actin depolymerization. Different modes of state transitions determine pattern in the Phosphatidylinositide-Actin system. BMC Cell Biol Periodic lamellipodial contractions correlate with rearward actin waves.
Mechanism and function of formins in the control of actin assembly. Integrin regulation of membrane domain trafficking and Rac targeting. Biochem Soc Trans Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Cell-matrix adhesions in 3D.
New insights into their functions from in vivo studies. Activated membrane patches guide chemotactic cell motility. PLoS Comput Biol 7: Cold Spring Harb Perspect Biol 4: Myosin IIb activity and phosphorylation status determines dendritic spine and post-synaptic density morphology.
The multifunctional GIT family of proteins. Chemotaxis in the absence of PIP3 gradients. Differential transmission of actin motion within focal adhesions. Integrins in cell migration. Regulation of cell migration by the calcium-dependent protease calpain.
Bidirectional, allosteric signaling machines. How cells direct motion in response to gradients. Tumor suppressor PTEN mediates sensing of chemoattractant gradients. Actin dynamics at the leading edge: From simple machinery to complex networks. Phosphoinositide signaling plays a key role in cytokinesis.
Chemoattractant-induced temporal and spatial PI 3,4,5 P 3 accumulation is controlled by a local excitation, global inhibition mechanism. Temporal and spatial regulation of phosphoinositide signaling mediates cytokinesis.
The clutch hypothesis revisited: Ascribing the roles of actin-associated proteins in filopodial protrusion in the nerve growth cone. Chemoattractants-induced Ras activation during Dictyostelium aggregation. Microtubule targeting of substrate contacts promotes their relaxation and dissociation. Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis. Regulators of the actin cytoskeleton and cell migration.
Localized Rac activation dynamics visualized in living cells. Reducing background fluorescence reveals adhesions in 3D matrices. PTEN regulates motility but not directionality during leukocyte chemotaxis. A physically integrated molecular process. TOR complex 2 integrates cell movement during chemotaxis and signal relay in Dictyostelium.
The tIPP of integrin signalling. Nat Rev Mol Cell Biol 7: Directional sensing in eukaryotic chemotaxis: A balanced inactivation model. Invadosomes in proteolytic cell invasion. TOR kinase complexes and cell migration. Coordination of Rho GTPase activities during cell protrusion. Signaling pathways in cell polarity. Actin-based cell motility and cell locomotion. Cytoskeletal dynamics and nerve growth.
In command and control of cell motility. Nat Rev Mol Cell Biol 6: Cell adhesion and polarity during immune interactions.
The tail of integrins, talin, and kindlins. Activation of endogenous Cdc42 visualized in living cells. Rho GTPases, dendritic structure, and mental retardation.
Tension is required but not sufficient for focal adhesion maturation without a stress fiber template. Calcium regulation of actin dynamics in dendritic spines. Physical mechanisms of signal integration by WASP family proteins. Integrin-ligand binding properties govern cell migration speed through cell-substratum adhesiveness.
G protein signaling events are activated at the leading edge of chemotactic cells. The first ten years. Integrating cytoskeletal dynamics and cellular tension. Review of the mechanism of processive actin filament elongation by formins. Cell Motil Cytoskeleton Nonpolarized signaling reveals two distinct modes of 3D cell migration. Cellular motility driven by assembly and disassembly of actin filaments. The drivers of actin assembly. Two distinct actin networks drive the protrusion of migrating cells.
Shining new light on 3D cell motility and the metastatic process. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Life at the leading edge.
Integrating signals from front to back. Mechanics and regulation of cytokinesis. Mol Cell Biol Spatiotemporal regulation of Ras-GTPases during chemotaxis.
Methods Mol Biol Force sensing by mechanical extension of the Src family kinase substrate pCas. Integrin-dependent and alternative adhesion mechanisms. Cell Tissue Res Mechanisms of gradient sensing and chemotaxis: Conserved pathways, diverse regulation. Integrins and extracellular matrix in mechanotransduction. Cold Spring Harb Perspect Biol 2: Assembly and signaling of adhesion complexes.
Curr Top Dev Biol Cold Spring Harb Perspect Med doi: The final steps of integrin activation: Phosphoinositides in cell architecture. Cold Spring Harb Perspect Biol doi: G protein signaling in yeast: New components, new connections, new compartments. The comings and goings of actin: Coupling protrusion and retraction in cell motility. A network of signaling pathways controls motility, directional sensing, and polarity.
Attraction of tip-growing pollen tubes by the female gametophyte. Curr Opin Plant Biol Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol Generation of cells that ignore the effects of PIP3 on cytoskeleton. The forces that shape the embryo , p. A key signal transducer downstream of the TCR.
Rho proteins, mental retardation and the neurobiological basis of intelligence. Prog Brain Res Signalling the way forward. Nat Rev Mol Cell Biol 5: Four key signaling pathways mediating chemotaxis in Dictyostelium discoideum. The leukocyte cytoskeleton in cell migration and immune interactions. Int Rev Cytol
Signaling Networks that Regulate Cell Migration
Cell migration is fundamental to establishing and maintaining the proper organization of multicellular organisms. Morphogenesis can be viewed as a. Having a fever helps T cells reach the site of infection, thanks to thermal sensing by heat shock proteins and induction of integrin-mediated T cell migration. Cell migration is an integrated multistep process that involves the coordination of complex biochemical and biomechanical signals to modulate cell morphology.