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Virtakoivu, R. What Is the Cytoskeleton Made Of? The cytoskeleton of eukaryotic cells is made of filamentous proteins, and it provides mechanical support to the cell and its cytoplasmic constituents.
All cytoskeletons consist of three major classes of elements that differ in size and in protein composition. Microtubules are the largest type of filament, with a diameter of about 25 nanometers nm , and they are composed of a protein called tubulin. Actin filaments are the smallest type, with a diameter of only about 6 nm, and they are made of a protein called actin.
Intermediate filaments, as their name suggests, are mid-sized, with a diameter of about 10 nm. Unlike actin filaments and microtubules, intermediate filaments are constructed from a number of different subunit proteins. What Do Microtubules Do? Figure 1. What Do Actin Filaments Do? Figure 2. What Do Intermediate Filaments Do? Figure 4: The structure of intermediate filaments. Intermediate filaments are composed of smaller strands in the shape of rods.
How Do Cells Move? The cytoskeleton of a cell is made up of microtubules, actin filaments, and intermediate filaments. These structures give the cell its shape and help organize the cell's parts. In addition, they provide a basis for movement and cell division. Cell Biology for Seminars, Unit 3. Topic rooms within Cell Biology Close. No topic rooms are there. Or Browse Visually.
Student Voices. Creature Cast. Simply Science. Green Screen. Green Science. Bio 2. The Success Code. Why Science Matters. The Beyond. Plant ChemCast. Postcards from the Universe. Brain Metrics. Mind Read. Interactions of vimentin filaments with focal adhesions can activate the MAPK pathway.
Vimentin phosphorylation induces vimentin disassembly and spatial reorientation, which regulates cell contraction and focal adhesion dynamics. Vimentin disassembly also releases CAS to affect actin dynamics. The interaction of vimentin with the adhesive cell structure is modulated by vimentin phosphorylation. PAK1-mediated vimentin phosphorylation at Ser leads to the spatial reorientation of vimentin filaments in smooth muscle cells, which may alter focal adhesion assembly [ 2 , 54 , 56 , 64 , 65 ].
As described earlier, cell contraction is critical for inducing retraction of the rear. In addition to focal contacts, vimentin intermediate filaments of smooth muscle attach to desmosomes on the plasma membrane and to dense bodies in the myoplasm.
The dense bodies are also the locations to which contractile actin filaments attach. Thus, the physical linkage of vimentin filaments to dense bodies provides the structural base by which vimentin intermediate filaments may modulate smooth muscle cell contraction.
Vimentin intermediate filaments are required for smooth muscle contraction. Our previous studies have shown that vimentin knockdown by antisense oligonucleotides inhibits smooth muscle force development [ 50 , 53 ].
Moreover, vimentin-deficient fibroblasts display impaired contractile capacity [ 55 ]. External stimulation induces vimentin phosphorylation at Ser, which leads to reorganization of the vimentin network, facilitating mechanical force transduction in smooth muscle. Vimentin phosphorylation at Ser is catalyzed by pactivated kinase 1 PAK1 and polo-like kinase 1 Plk1 in smooth muscle [ 50 , 52 , 67 , 68 ].
Vimentin dephosphorylation at this residue is regulated protein phosphatase 1 in smooth muscle [ 49 ] Fig. When cells move in a three-dimensional environment, the size of the nucleus influences the rate of migration. This is because the nucleus is the largest organelle inside the cell.
Thus, alterations of nucleus rigidity affect the cell ability to squeeze in between matrix fibers. Lamins are the type IV intermediate filament proteins that are the major components of the nuclear membrane [ 50 ] and largely affect the mechanical property of the nucleus.
Therefore, the impact of nuclear lamins on nucleus rigidity and invasion is dependent upon cancer cell types and local environment. Since lamins are present in muscle cells [ 73 ], it is likely that nuclear lamins affect nucleus rigidity and modulate smooth muscle cell migration in tissues, a three-dimensional environment.
The vimentin network is able to regulate the actin cytoskeleton in several ways. First, vimentin phosphorylation at Ser by PAK1 and Plk1 leads to its disassembly in smooth muscle, which results in the release of CAS from cytoskeletal vimentin. Second, caldesmon is a component of microfilaments in all cells and thin filaments in smooth muscle cells. Caldesmon is able to interact with intermediate filaments and polymerized actin, and is required for maintaining the intermediate filament network and actin filaments in smooth muscle cells [ 75 ].
As described earlier, increased expression of vimentin intermediate filaments enhances directed cell migration. Recent evidence suggests that the vimentin filament network assembles along the template of polarized microtubules. The longer-lived vimentin network then provides the template for future microtubule growth thus supporting and driving cell polarity and the directional persistence of migration [ 78 ].
This is further supported through previous micro-patterning studies showing that the vimentin filament network is crucial for microtubule organization, maintenance of cell polarity, and directional migration [ 79 ]. Microtubule assembly is a polarized process that starts from one or several microtubule organizing centers MTOCs. Typically, the centrosome serves as a major MTOC and stabilizes microtubule minus ends that are embedded in this complex structure.
The plus ends of microtubules point towards the cell periphery. Although microtubule elongation transpires at both plus and minus ends, it is more rapid at plus ends [ 80 ]. Microtubule restructuring have been shown to regulate smooth muscle cell migration [ 81 — 84 ].
Through their roles in mechanics, trafficking and signaling, microtubules regulate lamellipodial formation and focal adhesion dynamics. Moreover, microtubules undergo polarization during migration, which regulates migration-associated events in a spatial and temporal manner.
In motile cells, most microtubules do not enter lamellipodia; however, some microtubules, called pioneer microtubules, do extend to the protrusion sites. Because microtubules have ability to resist high compressive loads [ 85 ], it is likely that microtubule elongation in the protrusion may assist in pushing the membrane forward [ 80 , 81 ].
In addition, cytoplasmic linker associated proteins CLAPs may regulate microtubule assembly in the front of motile smooth muscle cells [ 81 ]. Microtubules may promote the delivery of membrane vesicles that are essential for cell protrusion [ 86 ]. Microtubules can deliver recycling endosomes carrying membrane-associated signaling molecules e. Moreover, microtubule assembly and disassembly are able to activate a growing number of GEFs to protrusion sites.
GEFs activate the small GTPases that promote actin mesh reorganization and lamellipodial formation [ 80 , 87 , 88 ] Fig. Cell migration regulated by microtubule-associated processes.
Microtubules regulate cell migration through their roles in mechanics, trafficking and signaling. Microtubules are able to facilitate nascent focal complex assembly in the leading edge. In addition, microtubules promote the polarized delivery of integrins to the leading-edge plasma membrane and participate in the growth of early focal adhesions [ 80 , 90 ]. In recent years, microtubules are found to interact with fascin an actin-binding and bundling protein , which contributes to fascin-dependent control of focal adhesion dynamics and cell migration speed [ 91 ].
Maturation of focal complexes in lamellipodia is facilitated by actomyosin-mediated contractile force. Microtubule depolymerization induces an increase in RhoA activity and cell contractility [ 92 ]. It is likely that changes in microtubule dynamics proximal to forming focal adhesions may locally increase cell contractility and, consequently, focal adhesion assembly [ 80 ].
RhoA-mediated contraction may also promote the retraction of the cell rear [ 80 ] Fig. Microtubules have been shown to trigger the disassembly of mature focal adhesions in the cell rear.
Treatment of cells with nocodazole results in the accumulation of integrins in mature focal adhesions, which is reversible after removal of nocodazole [ 80 , 92 ]. Dynamic microtubules recurrently target mature focal adhesions, which disassemble at the cell rear, by interacting with plus end tracking proteins [ 93 ]. Dynamin localizes at focal contacts and is required for focal adhesion disassembly in migrating cells, probably by promoting internalization of integrin complexes [ 94 ].
Dynamin also interacts with microtubules, which suggests that microtubules could deliver dynamin to focal adhesions to trigger intergrin-associated endosome internalization [ 80 , 95 ]. Moreover, quantitative proteomics suggest that mitogen-activated protein kinase kinase kinase kinase 4 MAP4K4 is a focal adhesion regulator that associates with microtubules.
Knockout of MAP4K4 stabilizes focal contacts and impairs cell migration. For directed migration to occur, microtubules are organized in a polarized manner to ensure spatial and temporal coordination of these events. In immobile cells, the microtubule framework is radially organized and shows no obvious polarization. In motile cells, the microtubule network is aligned with the axis of cell migration, which results from the orientation of the nucleus—centrosome axis parallel to the direction of migration, and from the organization of microtubules in an elongated and parallel array.
In most cells, microtubules accumulate toward the front of the cell and MTOCs localize in the front of the nucleus towards the direction of migration [ 80 , 93 ]. Polarization of the microtubule network facilitates trafficking of vesicles containing integrins and other molecules at the front to promote protrusion and focal contacts.
Polarized microtubules may also assist mature focal adhesion disassembly in the rear by transporting molecules such as dynamin and MAP4K4 [ 80 , 93 , 96 ]. It has been proposed that airway smooth muscle cell migration plays a role in the development of smooth muscle thickening in the asthmatic airways. Increases of the smooth muscle layer thickness in the asthmatic airways may be due to migration of smooth muscle cells in the muscle bundles [ 1 — 3 ]. In addition, there is evidence to suggest that vascular smooth muscle cell migration contributes to the progression of neointima formation after vascular injury [ 97 ].
Thus far, several biomolecules have been shown to regulate smooth muscle cell migration at least in part and the development of pulmonary and vascular diseases Table 1. Some of them have been used as biotargets to develop new therapies to treat lung and vascular diseases.
As described earlier, c-Abl tyrosine kinase positively orchestrates airway smooth muscle migration by modulating actin network reorganization [ 3 ].
To assess its role in vivo, we have generated c-Abl smooth muscle conditional knockout mice. Allergen exposure leads to increases in the thickness of the airway smooth muscle layer in mice, which is reduced in c-Abl conditional knockout mice [ 12 ].
Furthermore, the role of c-Abl in airway smooth muscle thickening is supported by using the c-Abl inhibitor imatinib [ 98 ]. These results suggest that c-Abl mediated smooth muscle migration participates in the development of airway remodeling in the asthmatic animals. There is evidence that p38 inhibition reduced airway smooth muscle cell migration.
Moreover, treatment with an inactive PAK1 attenuated p38 activation and airway smooth muscle migration [ 1 ]. Interestingly, inhibition of p38 suppressed airway remodeling in an animal model of asthma [ 99 ]. The roles of RhoA and Rho kinase in smooth muscle cell locomotion are well described [ 39 , 44 , 45 ]. Th2 cytokines could increase the expression of RhoA in airway smooth muscle [ ]. Treatment with RGD peptide blocks integrin activation and reduces airway remodeling in asthmatic animals [ ].
A common cortactin gene variation has been found to confer susceptibility of severe asthma [ ]. Since cortactin regulates smooth muscle cell protrusion formation [ 3 ], it is likely that cortactin-associated migration may contribute to asthma pathogenesis. Despite their involvement of cell migration, we do not know exactly how these proteins contribute to airway remodeling.
Smooth muscle cells play a critical role in the pathogenesis of vascular diseases and its clinical manifestations. Chronic pulmonary arterial hypertension is characterized by vascular remodeling. Treatment of the c-Abl inhibitor imatinib relieves the symptoms of a patient with pulmonary arterial hypertension [ ]. Results from Phase II and III clinical trials suggest that imatinib has potent and prolonged efficacy in patients with severe pulmonary arterial hypertension [ ].
Vascular remodeling is also a key feature of systemic hypertension. Pfn-1 [ ] and vimentin [ ] have been shown to mediate vascular remodeling in animal models. Pfn-1 knockdown inhibits arterial remodeling in hypertensive rats whereas overexpression of Pfn-1 promotes vascular remodeling [ ].
Flow-induced vascular remodeling may contribute to the development of hypertension. Flow-induced vascular remodeling is reduced in vimentin knockout mice [ ]. In addition to atherosclerosis, neointima formation is a major pathological process after percutaneous coronary intervention, bypass operation, or graft vasculopathy.
It has been widely accepted that intimal smooth muscle cells in proliferative vascular diseases are derived largely from resident medial smooth muscle cells [ 97 ].
Myosin light chain phosphorylation modulates cell contraction to facilitate smooth muscle cell migration [ 39 , 44 ]. In addition, c-Abl has been implicated in the pathogenesis of atherosclerosis; inhibition of c-Abl by imatinib attenuates the progression of diabetes-associated atherosclerosis [ ].
Furthermore, formin mDia1 has been shown to mediate neointima expansion in an animal model [ ]. Elucidating the mechanisms of smooth muscle cell migration is a hot topic in smooth muscle biology and asthma research. The actin-associated proteins are able to regulate actin branching, elongation, debranching, depolymerization, focal adhesion dynamics, and contraction.
The vimentin intermediate filament network undergoes phosphorylation and spatial reorganization in smooth muscle, which regulates its function in smooth muscle. More studies are required to investigate the role and mechanisms of the intermediate filament network in smooth muscle cell migration.
Although the role of microtubules in non-muscle cell motility has been described, their functions in smooth muscle cells remain to be elucidated. Furthermore, it will be very attractive to identify potential smooth muscle specific cell migration regulators that could be used to treat smooth muscle diseases such as asthma, hypertension, and vascular injury. Gerthoffer WT. Migration of airway smooth muscle cells.
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