Cell migration
Encyclopedia
Cell migration is a central process in the development and maintenance of multicellular organism
s. Tissue formation during embryonic development
, wound healing
and immune response
s all require the orchestrated movement of cells in particular directions to specific locations. Errors during this process have serious consequences, including mental retardation, vascular disease
, tumor formation
and metastasis
. An understanding of the mechanism by which cells migrate may lead to the development of novel therapeutic strategies for controlling, for example, invasive tumour cells. Cells often migrate in response to, and toward, specific external signals, a process called chemotaxis
.
films are taken so that a speeded up movie can be viewed. This shows that, although the shape of a moving cell varies considerably, its leading front has a characteristic behaviour. This region of the cell is highly active, sometimes spreading forward quickly, sometimes retracting, sometimes ruffling or bubbling. It is generally accepted that the leading front is the main motor that pulls the cell forward.
) has several common features, the underlying processes are believed to be similar. The two main constant features are:
The latter feature is most easily observed when aggregates of a surface molecule are cross-linked with a fluorescent antibody
(see cap formation
) or when small beads become artificially bound to the front of the cell.
Besides mammalian cells, many other eukaryotic cells appear to move in a similar way. One of the most valuable model creatures for studying locomotion and chemotaxis is the amoeba Dictyostelium discoideum
, because they move more quickly than most mammalian cells grown in the lab, and they chemotax toward cyclic AMP
. In addition, they have a haploid genome that assists understanding the role of a particular gene product in movement.
polymerisation: soluble actin monomers polymerise there to form filaments. This has led to the view that it is the formation of these actin filaments, which pushes the leading front forward and is the main motile force for advancing the cell’s front. In addition, cytoskeletal elements are able to interact extensively and intimately with a cell's plasma membrane.
. This has led to the view that extension of the leading edge occurs primarily by addition of membrane at the front of the cell. 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 the cell's blowing bubbles (or "blebs") at its front. For a cell to move, it is necessary to bring a fresh supply of "feet" (those molecules called integrins, which attach a cell to the surface on which it is crawling) to the 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.
and perhaps other large structures inside the cell may also be pulled forward by actin filaments. In addition, it may be that the rear of the cell actively contracts, as it is here that, in some cells, the major contractile protein myosin
is found.
, which affect migratory processes, these tend to fall into two groups: transcription factors (such as slow border cells (slbo), which affects the migration of the border cells) or key regulator proteins (such as C-Jun N-terminal kinases
(JNK), which controls dorsal closure). These, however, tell us little about how cells actually move.
Another major source of mutants is the haploid amoeba Dictyostelium. Many single-copy genes associated with cytoskeletal function have been deleted: These mutants usually have only a weak phenotype
, suggesting either that these genes are not required for locomotion, or that there are multiple mechanisms by which cells can move. However, temperature-sensitive mutants in the genes for N-ethylmaleimide sensitive fusion protein
(NSF) and Sec1 rapidly block cell migration indicating that the NSF protein and Sec1p are both required for some aspects of cell movement. NSF is known to function in intracellular membrane fusion; Sec1p in yeast is required for polarised exocytosis.
. Thus, the phospholipid PIP3
and activated Rac and CDC42
are found at the front of the cell, whereas Rho GTPase
and PTEN
are found toward the rear.
It is believed that microtubule
s and filamentous actin
are important for establishing and maintaining a cell’s polarity. Thus, drugs that destroy microtubules disrupt the polarity of many cells: If the cell is attached to a substratum, they often become round and flat. Drugs that destroy actin filaments have multiple and complex effects, reflecting the wide role that these filaments play in many cell processes. It may be that, as part of the locomotory process, membrane vesicles
are transported along these filaments to the cell’s front. 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 surface. And where these are located appears in turn to be determined by the chemoattractant signals as these impinge on specific receptor
s on the cell’s outer surface.
Multicellular organism
Multicellular organisms are organisms that consist of more than one cell, in contrast to single-celled organisms. Most life that can be seen with the the naked eye is multicellular, as are all animals and land plants.-Evolutionary history:Multicellularity has evolved independently dozens of times...
s. Tissue formation during embryonic development
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
, wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
and immune response
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
s all require the orchestrated movement of cells in particular directions to specific locations. Errors during this process have serious consequences, including mental retardation, vascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, tumor formation
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
and metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
. An understanding of the mechanism by which cells migrate may lead to the development of novel therapeutic strategies for controlling, for example, invasive tumour cells. Cells often migrate in response to, and toward, specific external signals, a process called chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
.
Studying cell migration
The migration of single mammalian cells is usually viewed in the microscope as the cells move randomly on a glass slide. As the actual movement is very slow — usually a few micrometers/minute — time-lapseTime-lapse
Time-lapse photography is a cinematography technique whereby the frequency at which film frames are captured is much lower than that which will be used to play the sequence back. When replayed at normal speed, time appears to be moving faster and thus lapsing...
films are taken so that a speeded up movie can be viewed. This shows that, although the shape of a moving cell varies considerably, its leading front has a characteristic behaviour. This region of the cell is highly active, sometimes spreading forward quickly, sometimes retracting, sometimes ruffling or bubbling. It is generally accepted that the leading front is the main motor that pulls the cell forward.
Common features
There is still great uncertainty of how cell migration really works. However, because the locomotion of all mammalian cells (except spermSpermatozoon
A spermatozoon is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote...
) has several common features, the underlying processes are believed to be similar. The two main constant features are:
- the behaviour of the leading front
- the observation that any debris on the dorsal surface of the cell moves backward on the cell’s surface toward its trailing end.
The latter feature is most easily observed when aggregates of a surface molecule are cross-linked with a fluorescent antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
(see cap formation
Cap formation
When molecules on the surface of a cell are crosslinked, they are moved to one end of the cell to form a “cap”. This phenomenon, the process of which is called cap formation, was discovered in 1971 on lymphocytes and is a property of amoebae and all locomotory animal cells except sperm. The...
) or when small beads become artificially bound to the front of the cell.
Besides mammalian cells, many other eukaryotic cells appear to move in a similar way. One of the most valuable model creatures for studying locomotion and chemotaxis is the amoeba Dictyostelium discoideum
Dictyostelium discoideum
Dictyostelium discoideum is a species of soil-living amoeba belonging to the phylum Mycetozoa. D. discoideum, commonly referred to as slime mold, is a eukaryote that transitions from a collection of unicellular amoebae into a multicellular slug and then into a fruiting body within its lifetime. D...
, because they move more quickly than most mammalian cells grown in the lab, and they chemotax toward cyclic AMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
. In addition, they have a haploid genome that assists understanding the role of a particular gene product in movement.
Molecular processes at the front
There are two main theories for how the cell advances its front edge: the cytoskeletal model and membrane flow model. It is possible that both underlying processes contribute to cell extension.Cytoskeletal model (A)
Through experiment, it is found that the cell's front is a site of rapid actinActin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
polymerisation: soluble actin monomers polymerise there to form filaments. This has led to the view that it is the formation of these actin filaments, which pushes the leading front forward and is the main motile force for advancing the cell’s front. In addition, cytoskeletal elements are able to interact extensively and intimately with a cell's plasma membrane.
Membrane flow model (B)
Studies have also shown that the front is the site at which membrane is returned to the cell surface from internal membrane pools at the end of the endocytic cycleEndocytic cycle
Most animal cells take up portions of their surface plasma membranes in a process called endocytosis. The main route of endocytosis is the coated pit, which buds into a cell to form a cytoplasmic vesicle — a clathrin-coated vesicle. The membrane so internalised is processed in a series of...
. This has led to the view that extension of the leading edge occurs primarily by addition of membrane at the front of the cell. 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 the cell's blowing bubbles (or "blebs") at its front. For a cell to move, it is necessary to bring a fresh supply of "feet" (those molecules called integrins, which attach a cell to the surface on which it is crawling) to the 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.
The nucleus and rear
Given that a cell’s front advances, what about the rest of the cell? Is it simply dragged forward, like a sack? We do not know, but there are suggestions that the nucleusCell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
and perhaps other large structures inside the cell may also be pulled forward by actin filaments. In addition, it may be that the rear of the cell actively contracts, as it is here that, in some cells, the major contractile protein myosin
Myosin
Myosins comprise a family of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other eukaryotic motility processes. They are responsible for actin-based motility. The term was originally used to describe a group of similar...
is found.
Mutants
Insight into how complex biological processes work can often be gleaned from a study of mutations. In the case of the intracellular mechanisms underlying cell movement, this has been largely unsuccessful. Thus, although many mutants are known in DrosophilaDrosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
, which affect migratory processes, these tend to fall into two groups: transcription factors (such as slow border cells (slbo), which affects the migration of the border cells) or key regulator proteins (such as C-Jun N-terminal kinases
C-Jun N-terminal kinases
c-Jun N-terminal kinases , were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet...
(JNK), which controls dorsal closure). These, however, tell us little about how cells actually move.
Another major source of mutants is the haploid amoeba Dictyostelium. Many single-copy genes associated with cytoskeletal function have been deleted: These mutants usually have only a weak phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
, suggesting either that these genes are not required for locomotion, or that there are multiple mechanisms by which cells can move. However, temperature-sensitive mutants in the genes for N-ethylmaleimide sensitive fusion protein
N-ethylmaleimide sensitive fusion protein
N-ethylmaleimide-sensitive factor, also known as NSF or N-ethylmaleimide sensitive fusion proteins, is an enzyme which in humans is encoded by the NSF gene.- Function :...
(NSF) and Sec1 rapidly block cell migration indicating that the NSF protein and Sec1p are both required for some aspects of cell movement. NSF is known to function in intracellular membrane fusion; Sec1p in yeast is required for polarised exocytosis.
Polarity in migrating cells
Migrating cells have a polarity—a front and a back. Without it, they would move in all directions at once, i.e. spread. How this arrow 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 surfaceCell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. Thus, the phospholipid PIP3
Phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol -triphosphate , abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases phosphorylation on phosphatidylinositol -bisphosphate .-Discovery:...
and activated Rac and CDC42
CDC42
Cell division control protein 42 homolog also known as CDC42 is a protein involved in regulation of the cell cycle. In humans, CDC42 is encoded by the CDC42 gene.- Function :...
are found at the front of the cell, whereas Rho GTPase
Rho GTPase
A Rho GTPase may refer to:*Any member of the Rho family of GTPases*The members of the Rho family of GTPases belonging to the Rho subclass*RhoA, the most-studied member of the Rho subclass of the Rho family of GTPases...
and PTEN
PTEN (gene)
Phosphatase and tensin homolog is a protein that, in humans, is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers....
are found toward the rear.
It is believed that microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
s and filamentous actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
are important for establishing and maintaining a cell’s polarity. Thus, drugs that destroy microtubules disrupt the polarity of many cells: If the cell is attached to a substratum, they often become round and flat. Drugs that destroy actin filaments have multiple and complex effects, reflecting the wide role that these filaments play in many cell processes. It may be that, as part of the locomotory process, membrane vesicles
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
are transported along these filaments to the cell’s front. 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 surface. And where these are located appears in turn to be determined by the chemoattractant signals as these impinge on specific receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s on the cell’s outer surface.
External links
- Cell Migration Gateway The Cell Migration Gateway is a comprehensive and regularly updated resource on cell migration
- http://cellix.imba.oeaw.ac.at/ Video tour of cell motility