Actin is a key protein in numerous cellular functions. One recent study has identified a large set of genes, associated with the actin cytoskeleton, which could be grouped into a wide spectrum of cytoplasmic and nuclear functions, such as protein biosynthesis and gene transcription.1 Deletions of many of the identified genes affected cellular actin organization,1 suggesting a functional link between different actin fractions probably regulated through changes in actin dynamics. The data are very exciting; (...) speculations on the crosstalk between cytoplasmic and nuclear actin fractions in different cellular contexts may help placing the results in perspective to further understand how actin‐mediated signalling affects cellular functions, such as gene expression. BioEssays 29:407–411, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The bacterial pathogen Listeria monocytogenes displays the remarkable ability to reorganize the actin cytoskeleton within host cells as a means for promoting cell‐to‐cell transfer of the pathogen, in a manner that evades humoral immunity. In a series of events commencing with the biosynthesis of the bacterial surface protein ActA, host cell actin and many actin‐associated protein self‐assemble to from rocket‐tail structures that continually grow at sites proximal to the bacterium and depolymerize distally. Widespread interest in the (...) underlying molecular mechanism of Listeria locomotion stems from the likelihood that the dynamic remodeling of the host cell actin cytoskeleton at the cell's leading edge involves mechanistically analogous interactions. Recent advances in our understanding of these fundamental cytoskeletal rearrangements have been achieved through a clearer recognition of the central role of oligo‐proline sequence repeats present in ActA, and these findings provide a basis for inferring the role of analogous host cell proteins in the force‐producing and position‐securing steps in pseudopod and lamellipod formation at the peripheral membrane. (shrink)

Despite its small size, profilin is an amazingly diverse and sophisticated protein whose precise role in cells continues to elude the understanding of researchers 15 years after its discovery. Its ubiquity, abundance and necessity for life in more evolved organisms certainly speaks for its exterme importance in cell function. So far, three ligands for profilin have been well‐characterized in vitro: actin monomers, membrane polyphosphoinositides and poly‐L‐proline. In the years following its discovery, profilin's role in vivo progressed from that of (...) a simple actin‐binding protein which inhibits actin polymerization, to one which, as an important regulator of the cytoskeleton, can even promote actin polymerization under the appropriate circumstances. In addition, interactions with components of the phosphatidylinositol cycle and the RAS pathway in yeast implicate profilin as an important link through which the actin cytoskeleton is able to communicate with major signaling pathways. (shrink)

Rnd3/RhoE has two distinct functions, regulating the actin cytoskeleton and cell proliferation. This might explain why its expression is often altered in cancer and by multiple stimuli during development and disease. Rnd3 together with its relatives Rnd1 and Rnd2 are atypical members of the Rho GTPase family in that they do not hydrolyse GTP. Rnd3 and Rnd1 both antagonise RhoA/ROCK‐mediated actomyosin contractility, thereby regulating cell migration, smooth muscle contractility and neurite extension. In addition, Rnd3 has been shown to (...) have a separate role in inhibiting cell cycle progression by reducing translation of cell cycle regulators, including cyclin D1 and Myc. We propose that Rnd3 could act as a tumour suppressor to limit proliferation, but when mutations bypass this activity of Rnd3, it can promote cancer invasion through its effects in the actin cytoskeleton. (shrink)

The Hippo pathway, a cascade of protein kinases that inhibits the oncogenic transcriptional coactivators YAP and TAZ, was discovered in Drosophila as a major determinant of organ size in development. Known modes of regulation involve surface proteins that mediate cell‐cell contact or determine epithelial cell polarity which, in a tissue‐specific manner, use intracellular complexes containing FERM domain and actin‐binding proteins to modulate the kinase activities or directly sequester YAP. Unexpectedly, recent work demonstrates that GPCRs, especially those signaling through Galpha12/13 (...) such as the protease activated receptor PAR1, cause potent YAP dephosphorylation and activation. This response requires active RhoA GTPase and increased assembly of filamentous (F‐)actin. Morever, cell architectures that promote F‐actin assembly per se also activate YAP by kinase‐dependent and independent mechanisms. These findings unveil the ability of GPCRs to activate the YAP oncogene through a newly recognized signaling function of the actin cytoskeleton, likely to be especially important for normal and cancerous stem cells. (shrink)

Coronins constitute an evolutionarily conserved family of WD‐repeat actin‐binding proteins, which can be clearly classified into two distinct groups based on their structural features. All coronins possess a conserved basic N‐terminal motif and three to ten WD repeats clustered in one or two core domains. Dictyostelium and mammalian coronins are important regulators of the actin cytoskeleton, while the fly Dpod1 and the yeast coronin proteins crosslink both actin and microtubules. Apart from that, several coronins have been (...) shown to be involved in vesicular transport. C. elegans POD‐1 and Drosophila coro regulate the actin cytoskeleton, but also govern vesicular trafficking as indicated by mutant phenotypes. In both organisms, defects in cytoskeleton and trafficking lead to severe developmental defects ranging from abnormal cell division to aberrant formation of morphogen gradients. Finally, mammalian coronin 7 appears not to execute any cytoskeleton‐related functions, but rather participates in regulating Golgi trafficking. Here, we review recent data providing more insight into molecular mechanisms underlying the regulation of F‐actin structures, cytoskeletal rearrangements and intracellular membrane transport by coronin proteins and the way that they might link cytoskeleton with trafficking in development and disease. BioEssays 27:625–632, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Receptor‐mediated stimulation induces massive actin polymerization and cyto‐skeletal reorganization. The activity of a potent actin‐modulating protein, gelsolin, is regulated both by Ca2+ and polyphos‐phoinositides, and it may have a pivotal role in restructuring the actin cytoskeleton in response to agonist stimulation. Structure‐function analysis of gelsolin has (1) indicated that its NH2‐terminal half is primarily responsible for modulating actin filament length and polymerization; and (2) elucidated mechanisms by which Ca2+ and phospholipids may regulate such functions. Gelsolin (...) is functionally and structurally similar to villin, another Ca2+‐activated actin‐severing protein found in microvilli, suggesting that gelsolin may be a prototype of this family of actin‐modulating proteins. A molecular variant of gelsolin is secreted and may be involved in the clearance of actin filaments released during tissue damage. The two forms of gelsolin are encoded by a single gene, and distinct messages are derived by alternative message splicing. (shrink)

A very rapid cellular event that follows chemotactic stimulation of leucocyte and cellular slime mould amoebae is a massive polymerization of G to F actin and its association with the cytoskeleton. In the cellular slime moulds this event occurs within 3–5 sec of cell surface binding of chemoattractants. It is correlated with rapid pseudopodium extension and may be a cell orientation mechanism. Curiously, before an amoebae moves away in the direction of its new pseudopodium it rounds up or (...) “cringes” for 10–20 sec, an event correlated with a massive actin depolymerization. Transduction of the chemotactic signal involves Ca2+ release from internal stores by inositol trisphosphate. (shrink)

Recent genetic manipulations have revealed that the cytoplasm of the early Drosophila embryo contains localized information that specifies the future embryonic axes. It is the restricted distribution or activity of particular gene products, either messenger RNA or protein, that is crucial for this specification. While some of the genes responsible for this information have been seqenced and the nature and distribution of their products examined, it is not known how this localization is established or maintained. The actin‐based cytoskeleton (...) is a likely candidate for the formation of a cytomatrix that would allow such distributions and yet no direct evidence has yet been found that implicates actin in positional cue localization. In this review I summarize what is known about actin filament behavior. in Drosophila embryos and compare it to the distribution of positional cues. My purpose is to juxtapose these two bodies of information such that the relationship between them may be revealed. (shrink)

The eukaryotic cytoskeleton appears to have evolved from ancestral precursors related to prokaryotic FtsZ and MreB. FtsZ and MreB show 40–50% sequence identity across different bacterial and archaeal species. Here I suggest that this represents the limit of divergence that is consistent with maintaining their functions for cytokinesis and cell shape. Previous analyses have noted that tubulin and actin are highly conserved across eukaryotic species, but so divergent from their prokaryotic relatives as to be hardly recognizable from sequence (...) comparisons. One suggestion for this extreme divergence of tubulin and actin is that it occurred as they evolved very different functions from FtsZ and MreB. I will present new arguments favoring this suggestion, and speculate on pathways. Moreover, the extreme conservation of tubulin and actin across eukaryotic species is not due to an intrinsic lack of variability, but is attributed to their acquisition of elaborate mechanisms for assembly dynamics and their interactions with multiple motor and binding proteins. A new structure‐based sequence alignment identifies amino acids that are conserved from FtsZ to tubulins. The highly conserved amino acids are not those forming the subunit core or protofilament interface, but those involved in binding and hydrolysis of GTP. BioEssays 29:668–677, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Spontaneous polarization without spatial cues, or symmetry breaking, is a fundamental problem of spatial organization in biological systems. This question has been extensively studied using yeast models, which revealed the central role of the small GTPase switch Cdc42. Active Cdc42‐GTP forms a coherent patch at the cell cortex, thought to result from amplification of a small initial stochastic inhomogeneity through positive feedback mechanisms, which induces cell polarization. Here, I review and discuss the mechanisms of Cdc42 activity self‐amplification and dynamic turnover. (...) A robust Cdc42 patch is formed through the combined effects of Cdc42 activity promoting its own activation and active Cdc42‐GTP displaying reduced membrane detachment and lateral diffusion compared to inactive Cdc42‐GDP. I argue the role of the actin cytoskeleton in symmetry breaking is not primarily to transport Cdc42 to the active site. Finally, negative feedback and competition mechanisms serve to control the number of polarization sites. (shrink)

The actin cytoskeleton is a key cellular structure subverted by pathogens to infect and survive in or on host cells. Several pathogenic strains of Escherichia coli, such as enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC), developed a unique mechanism to remodel the actin cytoskeleton that involves the assembly of actin filament‐rich pedestals beneath the bacterial attachment sites. Actin pedestal assembly is driven by bacterial effectors injected into the host cells, and this structure (...) is important for EPEC and EHEC colonization. While the interplay between bacterial effectors and the actin polymerization machinery of host cells is well‐understood, how other mechanisms of actin filament remodelling regulate pedestal assembly and bacterial attachment are poorly investigated. This review discusses the gaps in our understanding of the complexity of the actin cytoskeletal remodelling during EPEC and EHEC infection. We describe possible roles of actin depolymerizing, crosslinking and motor proteins in pedestal dynamics, and bacterial interactions with the host cells. We also discuss the biological significance of pedestal assembly for bacterial infection. (shrink)

The sites of tightest adhesion that form between cells and substrate surfaces in tissue culture are termed focal contacts. The external faces of focal contacts include specific receptors, belonging to the integrin family of proteins, for fibronectin and vitronectin, two common components of extracellular matrices. On the internal (cytoplasmic) side of focal contacts, several proteins, including talin and vinculin, mediate interactions with the actin filament bundles of the cytoskeleton. The changes that occur in focal contacts as a result (...) of viral transformation are discussed. (shrink)

This is a brief historical view, based on my personal experience, of the phenomenological study of the assembly of actin in Japan. The morphogenesis and dynamics of protein filaments and cytoskeleton now represent one of the central problems in cell biology. The approach to this problem at the molecular level was first undertaken on actin from muscle.

The LIM domain kinases (LIMKs) are important actin cytoskeleton regulators. These proteins, LIMK1 and LIMK2, are nodes downstream of Rho GTPases and are the key enzymes that phosphorylate cofilin/actin depolymerization factors to regulate filament severing. They therefore perform an essential role in cascades that control actin depolymerization. Signaling of the LIMKs is carefully regulated by numerous inter‐ and intra‐molecular mechanisms. In this review, we discuss recent findings that improve the understanding of LIM domain kinase regulation mechanisms. (...) We also provide an up‐to‐date review of the role of the LIM domain kinases, their architectural features, how activity is impacted by other proteins, and the implications of these findings for human health and disease. (shrink)

Cytoskeletal proteins provide the structural foundation that allows cells to exist in a highly organized manner. Recent evidence suggests that certain cytoskeletal proteins not only maintain structural integrity, but might also be associated with signal transduction and suppression of tumorigenesis. Since the time of the discovery of tensin, a fair amount of data has been gathered which supports the notion that tensin is one such protein possessing these characteristics. In this review, we discuss recent studies that: (1) elucidate a role (...) for tensin in maintenance of cellular structure and signal transduction; (2) implicate tensin as the anchor for actin filaments at the focal adhesion; (3) describe the phosphorylation of tensin; (4) describe potential targets for its Src homology region 2 domain; (5) describe the association between tensin and the nuclear protein p130; and (6) demonstrate that increased tensin expression in a cell line appears to reduce its transformation potential. (shrink)

Transient receptor potential vanilloid 4 (TRPV4), a member of the TRP superfamily, is a broadly expressed, cell surface‐localized cation channel that is activated by a variety of environmental stimuli. Importantly, TRPV4 has been increasingly implicated in the regulation of cellular morphology. Here we propose that TRPV4 and the cytoskeletal remodeling small GTPase RhoA together constitute an environmentally sensitive signaling complex that contributes to pathological cell cytoskeletal alterations during neurological injury and disease. Supporting this hypothesis is our recent work demonstrating direct (...) physical and bidirectional functional interactions of TRPV4 with RhoA, which can lead to activation of RhoA and reorganization of the actin cytoskeleton. Furthermore, a confluence of evidence implicates TRPV4 and/or RhoA in pathological responses triggered by a range of acute neurological insults ranging from stroke to traumatic injury. While initiated by a variety of insults, TRPV4–RhoA signaling may represent a common pathway that disrupts axonal regeneration and blood–brain barrier integrity. These insights also suggest that TRPV4 inhibition may represent a safe, feasible, and precise therapeutic strategy for limiting pathological TRPV4–RhoA activation in a range of neurological diseases. (shrink)

Physical forces regulate numerous biological processes during development, physiology, and pathology. Forces between the external environment and intracellular actin cytoskeleton are primarily transmitted through integrin‐containing focal adhesions and cadherin‐containing adherens junctions. Crosstalk between these complexes is well established and modulates the mechanical landscape of the cell. However, integrins and cadherins constitute large families of adhesion receptors and form multiple complexes by interacting with different ligands, adaptor proteins, and cytoskeletal filaments. Recent findings indicate that integrin‐containing hemidesmosomes oppose force transduction (...) and traction force generation by focal adhesions. The cytolinker plectin mediates this crosstalk by coupling intermediate filaments to the actin cytoskeleton. Similarly, cadherins in desmosomes might modulate force generation by adherens junctions. Moreover, mechanotransduction can be influenced by podosomes, clathrin lattices, and tetraspanin‐enriched microdomains. This review discusses mechanotransduction by multiple integrin‐ and cadherin‐based cell adhesion complexes, which together with the associated cytoskeleton form an integrated network that allows cells to sense, process, and respond to their physical environment. (shrink)

Focal adhesion kinase (FAK) is a nonreceptor protein‐tyrosine kinase implicated in controlling cellular responses to the engagement of cell‐surface integrins, including cell spreading and migration, survival and proliferation. Aberrant FAK signaling may contribute to the process of cell transformation by certain oncoproteins, including v‐Src. Progress toward elucidating the events leading to FAK activation following integrin‐mediated cell adhesion, as well as events downstream of FAK, has come through the identification of FAK phosphorylation sites and interacting proteins. A signaling partnership is formed (...) between FAK and Src‐family kinases, leading to tyrosine phosphorylation of FAK and associated ‘docking’ proteins Cas and paxillin. Subsequent recruitment of proteins containing Src homology 2 domains, including Grb2 and c‐Crk, to the complex is likely to trigger adhesion‐induced cellular responses, including changes to the actin cytoskeleton and activation of the Ras‐MAP kinase pathway. (shrink)

The generation of asymmetric cell shapes is a recurring theme in biology. In budding yeast, one form of cell asymmetry occurs for division and is generated by anisotropic growth of the mother cell to form a daughter cell bud. Previous genetic studies uncovered key roles for the small GTPase Cdc42 in organizing the actin cytoskeleton and vesicle delivery to the site of bud growth,1,2 but a recent paper has also raised questions about how control of Cdc42 activity is (...) integrated into a proposed hierarchical regulatory pathway that specifies a unique site of bud formation.3 BioEssays 25:833–836, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Over several years, genetic studies in the model system, Drosophila melanogastor, have uncovered genes that when mutated, lead to a block in myoblast fusion. Analyses of these gene products have suggested that Arp2/3‐mediated regulation of the actin cytoskeleton is crucial to myoblast fusion in the fly. Recent advances in imaging in Drosophila embryos, both in fixed and live preparations, have led to a new appreciation of both the three‐dimensional organization of the somatic mesoderm and the cell biology underlying (...) myoblast fusion. BioEssays 30:423–431, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The Rho GTPases—Rho, Rac and Cdc42—act as molecular switches, cycling between an active GTP‐bound state and an inactive GDP‐bound state, to regulate the actin cytoskeleton. It has recently become apparent that the Rho GTPases can be activated in subcellular zones that appear semi‐stable, yet are dynamically maintained. These Rho GTPase activity zones are associated with a variety of fundamental biological processes including symmetric and asymmetric cytokinesis and cellular wound repair. Here we review the basic features of Rho GTPase (...) activity zones, suggest that these zones represent a fundamental signaling mechanism, and discuss the implications of zone properties from the perspective of both their function and how they are likely to be controlled. BioEssays 28: 983–993, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Cadherin‐mediated cell‐cell adhesion is perturbed in protein tyrosine kinase (PTK)‐transformed cells. While cadherins themselves appear to be poor PTK substrates, their cytoplasmic binding partners, the Arm catenins, are excellent PTK substrates and therefore good candidates for mediating PTK‐induced changes in cadherin behavior. These proteins, p120ctn, β‐catenin and plakoglobin, bind to the cytoplasmic region of classical cadherins and function to modulate adhesion and/or bridge cadherins to the actin cytoskeleton. In addition, as demonstrated recently for β‐catenin, these proteins also have (...) crucial signaling roles that may or may not be related to their effects on cell‐cell adhesion. Tyrosine phosphorylation of cadherin complexes is well documented and widely believed to modulate cell adhesiveness. The data to date, however, is largely correlative and the mechanism of action remains unresolved. In this review, we discuss the current literature and suggest models whereby tyrosine phosphorylation of Arm catenins contribute to regulation or perturbation of cadherin function. (shrink)

There are many morphologically distinct membrane structures with different functions at the surface of epithelial cells. Among these, adherens junctions (AJ) and tight junctions (TJ) are responsible for the mechanical linkage of epithelial cells and epithelial barrier function, respectively. In the process of new cell–cell adhesion formation between two epithelial cells, such as after wounding, AJ form first and then TJ form on the apical side of AJ. This process is very complicated because AJ formation triggers drastic changes in the (...) organization of actin cytoskeleton, the activity of Rho family of small GTPases, and the lipid composition of the plasma membrane, all of which are required for subsequent TJ formation. In this review, the authors focus on the relationship between AJ and TJ as a representative example of specialization of plasma membrane regions and introduce recent findings on how AJ formation promotes the subsequent formation of TJ. (shrink)

The release of AlphaFold2 (AF2), a deep‐learning‐aided, open‐source protein structure prediction program, from DeepMind, opened a new era of molecular biology. The astonishing improvement in the accuracy of the structure predictions provides the opportunity to characterize protein systems from uncultured Asgard archaea, key organisms in evolutionary biology. Despite the accumulation in metagenomics‐derived Asgard archaea eukaryotic‐like protein sequences, limited structural and biochemical information have restricted the insight in their potential functions. In this review, we focus on profilin, an actin‐dynamics regulating (...) protein, which in eukaryotes, modulates actin polymerization through (1) direct actin interaction, (2) polyproline binding, and (3) phospholipid binding. We assess AF2‐predicted profilin structures in their potential abilities to participate in these activities. We demonstrate that AF2 is a powerful new tool for understanding the emergence of biological functional traits in evolution. (shrink)

Planar cell polarity (PCP)‐signaling and associated tissue polarization are evolutionarily conserved. A well documented feature of PCP‐signaling in vertebrates is its link to centriole/cilia positioning, although the relationship of PCP and ciliogenesis is still debated. A recent report in Drosophila established that Frizzled (Fz)‐PCP core signaling has an instructive input to polarized centriole positioning in non‐ciliated Drosophila wing epithelia as a PCP read‐out. Here, we review the impact of this observation in the context of recent descriptions of the relationship(s) of (...) core Fz‐PCP signaling and cilia/centriole positioning in epithelial and non‐epithelial cells. All existing data are consistent with a model where Fz‐PCP signaling functions upstream of centriole/cilia positioning, independent of ciliogenesis. The combined data sets indicate that the Fz‐Dsh PCP complex is instructive for centriole/ciliary positioning via an actin‐based mechanism. Thereby, centriole/cilia/centrosome positioning can be considered an evolutionarily conserved readout and common downstream effect of PCP‐signaling from flies to mammals. (shrink)

Cells in multicellular organisms often do not intermingle freely with each other. Differential cell affinities can contribute to organizing cells into different tissues. Drosophila limbs and the vertebrate central nervous system are subdivided into compartments. Cells in adjacent compartments do not mix. Cell interactions mediated by Notch-family receptors have been implicated in the specification of these compartment boundaries. Two recent reports analyze the role of the Notch signaling pathway in the generation of an affinity boundary in the Drosophila wing.1,2 The (...) first report1 analyzes the connection between Notch and the actin cytoskeleton. The second report2 analyzes the differential requirements of Notch and the transcription factor Supressor of Hairless in generating the affinity boundary. BioEssays 28: 113–116, 2006. © 2006 Wiley periodicals, Inc. (shrink)

One of the earliest structural changes observed in cells in response to many extracellular factors is membrane ruffling: the formation of motile cell surface protrusions containing a meshwork of newly polymerized actin filaments. It is becoming clear that actin reorganization is an integral part of early signal transduction pathways, and that many signalling molecules interact with the actin cytoskeleton. The small GTP‐binding protein Rac is a key regulator of membrane ruffling, and proteins that can regulate Rac (...) activity, such as Bcr, are likely to act on this signalling pathway. In addition, several previously characterized signal transducing molecules are implicated in the membrane‐ruffling response, including Ras, the adaptor protein Grb2, phosphatidyl inositol 3‐kinase, phospholipase A2 and phorbol ester‐responsive proteins. Changes in polyphosphoinositide metabolism and intracellular Ca2+ levels may also play a role. A number of actin‐binding and organizing proteins localize to membrane ruffles and are potential targets for these signal transducing molecules. (shrink)

Adherens junctions play pivotal roles in cell and tissue organization and patterning by mediating cell adhesion and cell signaling. These junctions consist of large multiprotein complexes that join the actin cytoskeleton to the plasma membrane to form adhesive contacts between cells or between cells and extracellular matrix. The best-known adherens junction is the zonula adherens (ZA) that forms a belt surrounding the apical pole of epithelial cells. Recent studies in Drosophila have further illuminated the structure of adherens junctions. (...) Scaffolding proteins encoded by the stardust gene are novel components of the Crumbs complex, which plays a critical role in ZA assembly.1-3 The small GTPase Rap1 controls the symmetric re-assembly of the ZA after cell division.4 Finally, the asymmetric distribution of adherens junction material regulates spindle orientation during asymmetric cell division in the sensory organ lineage.5 BioEssays 24:690–695, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The animal cell cytoskeleton consists of three interconnected filament systems: actin‐containing microfilaments (MFs), microtubules (MTs), and the lesser known intermediate filaments (IFs). All IF proteins share a common tripartite domain structure and the ability to assemble into 8–12 nm wide filaments. Electron microscopy data suggest that IFs are built according to a completely different plan from that of MFs and MTs. IFs are known to impart mechanical stability to cells and tissues but, until recently, the biomechanical properties of (...) single IFs were unknown. However, with the discovery of naturally occurring micrometer‐wide IF bundles and the development of new methodologies to mechanically probe single filaments, it is now possible to propose a more unified view of IF biomechanics. Unlike MFs and MTs, single IFs can now be described as flexible, extensible and tough, which has important implications for our understanding of cell and tissue mechanics. Furthermore, the molecular mechanisms at play when IFs are deformed point toward a pivotal role for them in mechanotransduction. BioEssays 29: 26–35, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

In vertebrate and invertebrate nonmuscle myosins, light‐ and heavy‐chain phosphorylation regulate myosin assembly into filaments, and interaction with actin. Vertebrate non‐muscle myosins can exist in vitro in three main states, either ‘folded’ (assembly‐blocked) or ‘extended’ (assembly‐competent) monomers, and filaments. Light‐chain phosphorylation regulates the ‘dynamic equilibrium’ between these states. The ability of the myosin to undergo changes in conformation and state of assembly may be an important mechanism in regulating the organization of the cytoskeleton and cell motility.

Many bacteria that cause disease have the capacity to enter into and live within eukaryotic cells such as epithelial cells and macrophages. The mechanisms used by these organisms to achieve and maintain this intracellular lifestyle vary considerably, but most mechanisms involve subversion and exploitation of host cell functions. Entry into non‐phagocytic cells involves triggering host signal transduction mechanisms to induce rearrangement of the host cytoskeleton, thereby facilitating bacterial uptake. Once inside the host cell, intracellular pathogens either remain within membrane (...) bound inclusions or escape to the cytoplasm. Those living in the cytoplasm can further pirate the host actin system, using actin as a mechanism to facilitate movement within and between host cells. Organisms remaining within the vacuole have specialized mechanisms for intracellular survival and growth which involve additional communication with the host cell. Some of the processes involved in the various steps of facultative intracellular parasitism are discussed in the context of subverting the host cell cytoskeleton and signal transduction pathways for bacterial benefit. (shrink)

Phagocytosis is an uptake of large particles governed by the actin-based cytoskeleton. Binding of particles to specific cell surface receptors is the first step of phagocytosis. In higher Eucaryota, the receptors able to mediate phagocytosis are expressed almost exclusively in macrophages, neutrophils, and monocytes, conferring immunodefence properties to these cells. Receptor clustering is thought to occur upon particle binding, that in turn generates a phagocytic signal. Several pathways of phagocytic signal transduction have been identified, including the activation of (...) tyrosine kinases and (or) serine/threonine kinase C in pivotal roles. Kinase activation leads to phosphorylation of the receptors and other proteins, recruited at the sites of phagocytosis. Monomeric GTPases of the Rho and ARF families are likely to be engaged downstream of activated receptors. The GTPases, in cooperation with phosphatidylinositol 4-phosphate 5-kinase and phosphatidylinositol 3-kinase lipid modifying enzymes, can modulate locally the assembly of the submembranous actin filament system leading to particle internalization. BioEssays 21:422–431, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Signal transduction via receptors for N‐formylmethionyl peptide chemoattractants (FPR) on human neutrophils is a highly regulated process which involves participation of cytoskeletal elements. Evidence exists suggesting that the cytoskeleton and/or the membrane skeleton controls the distribution of FPR in the plane of the plasma membrane, thus controlling the accessibility of FPR to different proteins in functionally distinct domains. In desensitized cells, FPR are restricted to domains which are depleted of G proteins but enriched in cytoskeletal proteins such as (...) class='Hi'>actin and fodrin. Thus, the G protein signal transduction partners of FPR become inaccessible to the agonist‐occupied receptor, preventing cell activation. The mechanism of interaction of FPR with the membrane skeleton is poorly understood but evidence is accumulating that suggests a direct binding of FPR (and other receptors) to cytoskeletal proteins such as actin. (shrink)

The present study is an attempt to relate the multicomponent response of the cytoskeleton (CSK), evaluated in twisted living adherent cells, to the heterogeneity of the cytoskeletal structure - evaluated both experimentally by means of 3D reconstructions, and theoretically considering the predictions given by two tensegrity models composed of (four and six) compressive elements and (respectively 12 and 24) tensile elements. Using magnetic twisting cytometry in which beads are attached to integrin receptors linked to the actin CSK of (...) living adherent epithelial cells, we specifically measured the elastic CSK response at quasi equilibrium state and partitioned this response in terms of cortical and cytosolic contributions with a two-component model (i.e., a series of two Voigt bodies). These two CSK components were found to be prestressed and exhibited a stress-hardening response which both characterize tensegrity behaviour with however significant differences: compared to the cytosolic component, the cortical cytoskeleton appears to be a faster responding component, being a less prestressed and easily deformable structure. The discrepancies in elastic behaviour between the cortical and cytosolic CSK components may be understood on the basis of prestress tensegrity model predictions, given that the length and number of constitutive actin elements are taken into account. (shrink)

Intermediate filaments (IFs) formed by vimentin are less understood than their cytoskeletal partners, microtubules and F‐actin, but the unique physical properties of IFs, especially their resistance to large deformations, initially suggest a mechanical function. Indeed, vimentin IFs help regulate cell mechanics and contractility, and in crowded 3D environments they protect the nucleus during cell migration. Recently, a multitude of studies, often using genetic or proteomic screenings show that vimentin has many non‐mechanical functions within and outside of cells. These include (...) signaling roles in wound healing, lipogenesis, sterol processing, and various functions related to extracellular and cell surface vimentin. Extracellular vimentin is implicated in marking circulating tumor cells, promoting neural repair, and mediating the invasion of host cells by viruses, including SARS‐CoV, or bacteria such as Listeria and Streptococcus. These findings underscore the fundamental role of vimentin in not only cell mechanics but also a range of physiological functions. Also see the video abstract here https://youtu.be/YPfoddqvz-g. (shrink)

Williams Syndrome is a developmental disorder that is characterized by cardiovascular problems, particular facial features and several typical behavioral and neurological abnormalities. In Williams Syndrome patients, a heterozygous deletion is present of a region on chromosome 7q11.23 (the Williams Syndrome critical region), which spans approximately 20 genes. Two of these genes encode proteins that regulate dynamic aspects of the cytoskeleton of the cell, either via the actin filament system (LIM kinase 1, or LIMK1), or through the microtubule network (...) (cytoplasmic linker protein of 115 kDa, or CLIP‐115). The recent findings that knockout mice lacking LIMK1 or CLIP‐115 have distinct neurological and behavioural phenotypes, indicates that cytoskeletal defects might play a role in the development of neurological symptoms in Williams Syndrome patients. In this review, we discuss the properties of LIMK and CLIP family proteins, their function in the regulation of the actin and microtubule cytoskeletal systems, respectively, and the relationship with neurodevelopmental aspects of Williams Syndrome. BioEssays 26:141–150, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

During morphogenesis, tissues undergo extensive remodeling to get their final shape. Such precise sculpting requires the application of forces generated within cells by the cytoskeleton and transmission of these forces through adhesion molecules within and between neighboring cells. Within individual cells, microtubules together with actomyosin filaments and intermediate filaments form the composite cytoskeleton that controls cell mechanics during tissue rearrangements. While studies have established the importance of actin‐based mechanical forces that are coupled via intercellular junctions, relatively little (...) is known about the contribution of other cytoskeletal components such as microtubules to cell mechanics during morphogenesis. In this review the focus is on recent findings, highlighting the direct mechanical role of microtubules beyond its well‐established role in trafficking and signaling during tissue formation. (shrink)

Identification of the molecular mechanisms underlying axonal branching in vivo has begun in several neuronal systems, notably the projections formed by dorsal root ganglion (DRG) neurons or retinal ganglion cells (RGC). cGMP signalling is essential for sensory axon bifurcation at the spinal cord, whereas brain‐derived neurotrophic factor (BDNF) and ephrinA signalling establish position‐dependent branching of RGC axons. In the latter system, the degradation of specific signalling components, via the ubiquitin‐proteasome system, may provide an additional mechanism involved in axon branching of (...) RGC. The process of arborisation is essential for neurons to innervate multiple targets and to build topographic maps. The various forms of branching found in different types of neurons are regulated by distinct signalling pathways activated by multiple extracellular cues in addition to axonal guidance factors. These signalling cascades, together with transcriptional programs, most likely interact and trigger the polymerisation or depolymerisation of the actin and tubulin cytoskeleton to regulate branching. (shrink)

One of the profound changes in cellular morphology during mitosis is a massive alteration in the organization of microfilament cytoskeleton. It has been recently discovered that nonmuscle caldesmon, an actin and calmodulin binding microfilament‐associated protein of relative molecular mass Mr = 83000, is dissociated from microfilaments during mitosis, apparently as a consequence of mitosis‐specific phosphorylation. cdc2 kinase, which is a catalytic subunit of MPF (maturation or mitosis promoting factor), is found to be responsible for the mitosis‐specific phosphorylation of (...) caldesmon. Because caldesmon is implicated in the regulation of actin myosin interactions and/or microfilament organization, these results suggest that cdc2 kinase directly affects microfilament re‐organization during mitosis. (shrink)

Several molecular mechanisms contribute directly and mechanically to the loss of epithelial phenotype. During epithelial–mesenchymal transition (EMT), adherens junctions and desmosomes are at least partially dissociated. At the same time, a massive cytoskeleton reorganization takes place, involving the rho family and the remodeling of the actin microfilament mesh. Numerous pathways have been described in vitro that control phenotype transition in specific cell models. In vivo developmental studies suggest that transcriptional control, activated by a specific pathway involving Ras, Src (...) and potentially the Wnt pathway, is an essential step. Recent functional and localization experiments indicate that the slug/snail family of transcription factors functions overall as an epithelial phenotype repressor and could represent a key EMT contributor. BioEssays 23:912–923, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Cell shape and cell contacts are determined by transmembrane receptor‐mediated associations of the cytoskeleton with specific extracellular matrix proteins and with ligands on the surface of adjacent cells. The cytoplasmic domains of these microfilament‐membrane associations at the adherens junction sites, also Iocalize a variety of regulatory molecules involved in signal transduction and gene regulation. The stimulation of cells with soluble polypeptide factors leads to rapid changes in cell shape and microfilament component organization. In addition, this stimulation also activates the (...) phosphoinositide signaling pathway. Recently, a linkage between actin‐binding proteins and the phosphoinositide signaling pathway, was discovered. It is Suggested that by the association with the second messenger system, and/or by controlling the localization of regulatory molecules, the cytoskeleton may regulate gene expression. (shrink)

Smooth muscle cells have developed a contractile machinery that allows them to exert tension on the surrounding extracellular matrix over their entire length. This has been achieved by coupling obliquely organized contractile filaments to a more‐or‐less longitudinal framework of cytoskeletal elements. Earlier structural data suggested that the cytoskeleton was composed primarily of intermediate filaments and played only a passive role. More recent findings highlight the segregation of actin isotypes and of actin‐associated proteins between the contractile and cytoskeletal (...) domains and raise the possibility that the cytoskeleton performs a more active function. Current efforts focus on defining the relative contributions of myosin cross‐bridge cycling and actin‐associated protein interactions to the maintenance of tension in smooth muscle tissue. (shrink)

A diverse family of proteins has been discovered with a small C‐terminal KASH domain in common. KASH domain proteins are localized uniquely to the outer nuclear envelope, enabling their cytoplasmic extensions to tether the nucleus to actin filaments or microtubules. KASH domains are targeted to the outer nuclear envelope by SUN domains of inner nuclear envelope proteins. Several KASH protein genes were discovered as mutant alleles in model organisms with defects in developmentally regulated nuclear positioning. Recently, KASH‐less isoforms have (...) been found that connect the cytoskeleton to organelles other than the nucleus. A widened view of these proteins is now emerging, where KASH proteins and their KASH‐less counterparts are cargo‐specific adaptors that not only link organelles to the cytoskeleton but also regulate developmentally specific organelle movements. BioEssays 27:1136–1146, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

In a companion review1 we discussed the data supporting the conclusion that at least two subtypes of spectrin exist in mammalian brain. One form is found in the cell bodies, dendrites, and post‐synaptic terminals of neurons (brain spectrin(240/235E)) and the other subtype is located in the axons and presynaptic terminals (brain spectrin(240/235)). Our recent understanding of brain spectrin subtype localization suggests a possible explanation for a conundrum concerning brain 4.1 localization. Amelin, an immunoreactive analogue of red blood cell (rbc) cytoskeletal (...) protein 4.1, is localized in neuronal cell bodies and dendrites when brain sections are stained with antibody against rbc protein 4.1. However, it has recently been suggested that synapsin I, a neuron‐specific phosphoprotein associated with the cytoplasmic surface of small synaptic vesicles, is related to erythrocyte 4.1. In this review we hypothesize that there are at least two forms of brain 4.1: a cell body/dendritic form (amelin) which is detected with rbc protein 4.1 antibody, and a unique form found exclusively in the presynaptic terminal (synapsin I). The binding of synapsin I to brain spectrin(240/235), and its ability to stimulate the spectrin/F‐actin interaction in a phosphorylation‐dependent manner suggests a model for the regulation of synaptic transmission mediated by the neuronal cytoskeleton. (shrink)

The fields of quantum biology and physics are now starting to unite to solve the mysteries associated with the field of evolutionary biology. One such question is the origination and propagation of consciousness which has always been ambiguous and in order to understand this concept, many theories have been proposed by several philosophers and scientists. This review paper agrees with the idea, that evolution is not a random process but hypothesizes, that its succession was managed by the expanding level of (...) consciousness due to cell division and cell differentiation. Several theories propose that the cytoskeleton and its proteins are promoters for consciousness in the brain, which propagates by means of super-conductance. A better correlation of cytoskeletal evolution and consciousness could help solve the enigma of the origination, propagation and existence of consciousness. This review is a compilation of theories, evidences and scientific studies which intends to bring an association between propagation of consciousness and the evolution of the cytoskeleton and its proteins. (shrink)

During immune responses against invading pathogenic bacteria, the cytoskeleton network enables macrophages to implement multiple essential functions. To protect the host from infection, macrophages initially polarize to adopt different phenotypes in response to distinct signals from the microenvironment. The extracellular stimulus regulates the rearrangement of the cytoskeleton, thereby altering the morphology and migratory properties of macrophages. Subsequently, macrophages degrade the extracellular matrix (ECM) and migrate toward the sites of infection to directly contact invading pathogens, during which the involvement (...) of cytoskeleton‐based structures such as podosomes and lamellipodia is indispensable. Ultimately, macrophages execute the function of phagocytosis to engulf and eliminate the invading pathogens. Phagocytosis is a complex process that requires the cooperation of cytoskeleton‐enriched super‐structures, such as filopodia, lamellipodia, and phagocytic cup. This review presents an overview of cytoskeletal regulations in macrophage polarization, ECM degradation, migration, and phagocytosis, highlighting the pivotal role of the cytoskeleton in host defense against infection. (shrink)

Extensive progress has been made recently in understanding the mechanism by which cells move and extend protrusions using site‐directed polymerization of actin in response to signalling. Insights into the molecular mechanism of production of force and movement by actin polymerization have been provided by a crosstalk between several disciplines, including biochemistry, biomimetic approaches and computational studies. This review focuses on the biochemical properties of the proteins involved in actin‐based motility and shows how these properties are used to (...) generate models of force production, how the predictions of different theoretical models are tested using a biochemically controlled reconstituted motility assay and how the changes in motility resulting from changes to the concentrations of components of the assay can help understand diverse aspects of the motile behavior of living cells. BioEssays 25:336–345, 2003. © 2003 Wiley Periodicals, Inc. (shrink)