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The Journal of Medical Investigation :... 2017The adherens junction (AJ) is a cadherin-based and actin filament associated cell-to-cell junction. AJs can contribute to tissue morphogenesis and homeostasis and their... (Review)
Review
The adherens junction (AJ) is a cadherin-based and actin filament associated cell-to-cell junction. AJs can contribute to tissue morphogenesis and homeostasis and their association with actin filaments is crucial for the functions. There are three types of AJs in terms of the mode of actin filament/AJ association. Among many actin-binding proteins associated with AJs, α-catenin is one of the most important actin filament/AJ linkers that functions in all types of AJs. Although α-catenin in cadherin-catenin complex appears to bind to actin filaments within cells, it fails to bind to actin filaments in vitro mysteriously. Recent report revealed that α-catenin in the complex can bind to actin filaments in vitro when forces are applied to the filament. In addition to force-sensitive vinculin binding, α-catenin has another force-sensitive property of actin filament-binding. Elucidation of its significance and the molecular mechanism is indispensable for understanding AJ formation and maintenance during tissue morphogenesis, function and repair. J. Med. Invest. 64: 14-19, February, 2017.
Topics: Actin Cytoskeleton; Actins; Adherens Junctions; Animals; Humans; Protein Binding; Protein Interaction Domains and Motifs; alpha Catenin
PubMed: 28373611
DOI: 10.2152/jmi.64.14 -
International Journal of Molecular... Mar 2022Ezrin is one of the members of the ezrin/radixin/moesin (ERM) family of proteins. It was originally discovered as an actin-binding protein in the microvilli structure... (Review)
Review
Ezrin is one of the members of the ezrin/radixin/moesin (ERM) family of proteins. It was originally discovered as an actin-binding protein in the microvilli structure about forty years ago. Since then, it has been revealed as a key protein with functions in a variety of fields including cell migration, survival, and signal transduction, as well as functioning as a structural component. Ezrin acts as a cross-linker of membrane proteins or phospholipids in the plasma membrane and the actin cytoskeleton. It also functions as a platform for signaling molecules at the cell surface. Moreover, ezrin is regarded as an important target protein in cancer diagnosis and therapy because it is a key protein involved in cancer progression and metastasis, and its high expression is linked to poor survival in many cancers. Small molecule inhibitors of ezrin have been developed and investigated as candidate molecules that suppress cancer metastasis. Here, we wish to comprehensively review the roles of ezrin from the pathophysiological points of view.
Topics: Actin Cytoskeleton; Actins; Cell Membrane; Cytoskeletal Proteins; Microfilament Proteins; Phosphoproteins
PubMed: 35328667
DOI: 10.3390/ijms23063246 -
Anatomical Record (Hoboken, N.J. : 2007) Dec 2018Actin is one of the most abundant intracellular proteins, essential in every eukaryotic cell type. Actin plays key roles in tissue morphogenesis, cell adhesion, muscle... (Review)
Review
Actin is one of the most abundant intracellular proteins, essential in every eukaryotic cell type. Actin plays key roles in tissue morphogenesis, cell adhesion, muscle contraction, and developmental reprogramming. Most actin studies have focused on its regulation at the protein level, either directly or through differential interactions with over a hundred intracellular binding partners. However, numerous studies emerging in recent years demonstrate specific types of nucleotide-level regulation that strongly affect non-muscle actins during cell migration and adhesion and are potentially applicable to other members of the actin family. This regulation involves zipcode-mediated actin mRNA targeting to the cell periphery, proposed to mediate local synthesis of actin at the cell leading edge, as well as the recently discovered N-terminal arginylation that specifically targets non-muscle β-actin via a nucleotide-dependent mechanism. Moreover, a study published this year suggests that actin's essential roles at the organismal level may be entirely nucleotide-dependent. This review summarizes the emerging data on actin's nucleotide-level regulation. Anat Rec, 301:1991-1998, 2018. © 2018 Wiley Periodicals, Inc.
Topics: Actin Cytoskeleton; Actins; Amino Acid Sequence; Animals; Humans; Protein Biosynthesis; Protein Processing, Post-Translational; RNA Interference
PubMed: 30312009
DOI: 10.1002/ar.23958 -
The FEBS Journal May 2023The actin cytoskeleton orchestrates cell mechanics and facilitates the physical integration of cells into tissues, while tissue-scale forces and extracellular rigidity...
The actin cytoskeleton orchestrates cell mechanics and facilitates the physical integration of cells into tissues, while tissue-scale forces and extracellular rigidity in turn govern cell behaviour. Here, we discuss recent evidence that actin filaments (F-actin), the core building blocks of the actin cytoskeleton, also serve as molecular force sensors. We delineate two classes of proteins, which interpret forces applied to F-actin through enhanced binding interactions: 'mechanically tuned' canonical actin-binding proteins, whose constitutive F-actin affinity is increased by force, and 'mechanically switched' proteins, which bind F-actin only in the presence of force. We speculate mechanically tuned and mechanically switched actin-binding proteins are biophysically suitable for coordinating cytoskeletal force-feedback and mechanical signalling processes, respectively. Finally, we discuss potential mechanisms mediating force-activated actin binding, which likely occurs both through the structural remodelling of F-actin itself and geometric rearrangements of higher-order actin networks. Understanding the interplay of these mechanisms will enable the dissection of force-activated actin binding's specific biological functions.
Topics: Actins; Actin Cytoskeleton; Cytoskeleton; Microfilament Proteins; Protein Binding; Mechanotransduction, Cellular
PubMed: 35778931
DOI: 10.1111/febs.16568 -
Trends in Cell Biology Oct 2014The actin cytoskeleton assembles into branched networks or bundles to generate mechanical force for critical cellular processes such as establishment of polarity,... (Review)
Review
The actin cytoskeleton assembles into branched networks or bundles to generate mechanical force for critical cellular processes such as establishment of polarity, adhesion, and migration. Stress fibers (SFs) are contractile actomyosin structures that physically couple to the extracellular matrix through integrin-based focal adhesions (FAs), thereby transmitting force into and across the cell. Recently, LIN-11, Isl1, and MEC-3 (LIM) domain proteins have been implicated in mediating this cytoskeletal mechanotransduction. Among the more well-studied LIM domain adapter proteins is zyxin, a dynamic component of both FAs and SFs. Here we discuss recent research detailing the mechanisms by which SFs adjust their structure and composition to balance mechanical forces and suggest ways that zyxin and other LIM domain proteins mediate mechanoresponse.
Topics: Actin Cytoskeleton; Animals; Humans; LIM-Homeodomain Proteins; Mechanotransduction, Cellular; Stress, Mechanical
PubMed: 24933506
DOI: 10.1016/j.tcb.2014.04.009 -
Journal of Plant Research Mar 2017ACTIN DEPOLYMERIZING FACTOR (ADF) is a conserved protein among eukaryotes. The main function of ADF is the severing and depolymerizing filamentous actin (F-actin), thus... (Review)
Review
ACTIN DEPOLYMERIZING FACTOR (ADF) is a conserved protein among eukaryotes. The main function of ADF is the severing and depolymerizing filamentous actin (F-actin), thus regulating F-actin organization and dynamics and contributing to growth and development of the organisms. Mammalian genomes contain only a few ADF genes, whereas angiosperm plants have acquired an expanding number of ADFs, resulting in the differentiation of physiological functions. Recent studies have revealed functions of ADFs in plant growth and development, and various abiotic and biotic stress responses. In biotic stress responses, ADFs are involved in both susceptibility and resistance, depending on the pathogens. Furthermore, recent studies have highlighted a new role of ADF in the nucleus, possibly in the regulation of gene expression. In this review, I will summarize the current status of plant ADF research and discuss future research directions.
Topics: Actin Cytoskeleton; Destrin; Plant Proteins; Plants
PubMed: 28044231
DOI: 10.1007/s10265-016-0899-8 -
Philosophical Transactions of the Royal... Dec 2016Self-assembly of two important components of the cytoskeleton of eukaryotic cells, actin microfilaments and microtubules (MTs) results in polar filaments of one... (Review)
Review
Self-assembly of two important components of the cytoskeleton of eukaryotic cells, actin microfilaments and microtubules (MTs) results in polar filaments of one chirality. As is true for bacterial flagella, in actin microfilaments, screw direction is important for assembly processes and motility. For MTs, polar orientation within the cell is paramount. The alignment of these elements in the cell cytoplasm gives rise to emergent properties, including the potential for cell differentiation and specialization. Complex MTs with a characteristic chirality are found in basal bodies and centrioles; this chirality is preserved in cilia. In motile cilia, it is reflected in the direction of the effective stroke. The positioning of the basal body or cilia on the cell surface depends on polarity proteins. In evolution, survival depends on global polarity information relayed to the cell in part by orientation of the MT and actin filament cytoskeletons and the chirality of the basal body to determine left and right coordinates within a defined anterior-posterior cell and tissue axis.This article is part of the themed issue 'Provocative questions in left-right asymmetry'.
Topics: Actin Cytoskeleton; Biological Evolution; Cytoskeleton; Eukaryotic Cells; Microtubules
PubMed: 27821520
DOI: 10.1098/rstb.2015.0408 -
Cell Jun 2024Integrins link the extracellular environment to the actin cytoskeleton in cell migration and adhesiveness. Rapid coordination between events outside and inside the cell...
Integrins link the extracellular environment to the actin cytoskeleton in cell migration and adhesiveness. Rapid coordination between events outside and inside the cell is essential. Single-molecule fluorescence dynamics show that ligand binding to the bent-closed integrin conformation, which predominates on cell surfaces, is followed within milliseconds by two concerted changes, leg extension and headpiece opening, to give the high-affinity integrin conformation. The extended-closed integrin conformation is not an intermediate but can be directly accessed from the extended-open conformation and provides a pathway for ligand dissociation. In contrast to ligand, talin, which links the integrin β-subunit cytoplasmic domain to the actin cytoskeleton, modestly stabilizes but does not induce extension or opening. Integrin activation is thus initiated by outside-in signaling and followed by inside-out signaling. Our results further imply that talin binding is insufficient for inside-out integrin activation and that tensile force transmission through the ligand-integrin-talin-actin cytoskeleton complex is required.
Topics: Animals; Humans; Mice; Actin Cytoskeleton; Cell Adhesion; CHO Cells; Cricetulus; Integrins; Ligands; Protein Binding; Protein Conformation; Signal Transduction; Single Molecule Imaging; Talin
PubMed: 38772370
DOI: 10.1016/j.cell.2024.04.049 -
Current Opinion in Cell Biology Apr 2024The cytoskeleton, comprising actin microfilaments, microtubules, and intermediate filaments, is crucial for cell motility and tissue integrity. While prior studies... (Review)
Review
The cytoskeleton, comprising actin microfilaments, microtubules, and intermediate filaments, is crucial for cell motility and tissue integrity. While prior studies largely focused on individual cytoskeletal networks, recent research underscores the interconnected nature of these systems in fundamental cellular functions like adhesion, migration, and division. Understanding the coordination of these distinct networks in both time and space is essential. This review synthesizes current findings on the intricate interplay between these networks, emphasizing the pivotal role of intermediate filaments. Notably, these filaments engage in extensive crosstalk with microfilaments and microtubules through direct molecular interactions, cytoskeletal linkers, and molecular motors that form molecular bridges, as well as via more complex regulation of intracellular signaling.
Topics: Intermediate Filaments; Cytoskeleton; Microtubules; Actin Cytoskeleton; Cell Movement; Actins
PubMed: 38359728
DOI: 10.1016/j.ceb.2024.102325 -
Nature Nov 2022ATP-hydrolysis-coupled actin polymerization is a fundamental mechanism of cellular force generation. In turn, force and actin filament (F-actin) nucleotide state...
ATP-hydrolysis-coupled actin polymerization is a fundamental mechanism of cellular force generation. In turn, force and actin filament (F-actin) nucleotide state regulate actin dynamics by tuning F-actin's engagement of actin-binding proteins through mechanisms that are unclear. Here we show that the nucleotide state of actin modulates F-actin structural transitions evoked by bending forces. Cryo-electron microscopy structures of ADP-F-actin and ADP-P-F-actin with sufficient resolution to visualize bound solvent reveal intersubunit interfaces bridged by water molecules that could mediate filament lattice flexibility. Despite extensive ordered solvent differences in the nucleotide cleft, these structures feature nearly identical lattices and essentially indistinguishable protein backbone conformations that are unlikely to be discriminable by actin-binding proteins. We next introduce a machine-learning-enabled pipeline for reconstructing bent filaments, enabling us to visualize both continuous structural variability and side-chain-level detail. Bent F-actin structures reveal rearrangements at intersubunit interfaces characterized by substantial alterations of helical twist and deformations in individual protomers, transitions that are distinct in ADP-F-actin and ADP-P-F-actin. This suggests that phosphate rigidifies actin subunits to alter the bending structural landscape of F-actin. As bending forces evoke nucleotide-state dependent conformational transitions of sufficient magnitude to be detected by actin-binding proteins, we propose that actin nucleotide state can serve as a co-regulator of F-actin mechanical regulation.
Topics: Actin Cytoskeleton; Actins; Adenosine Diphosphate; Cryoelectron Microscopy; Microfilament Proteins; Solvents; Machine Learning; Protein Conformation
PubMed: 36289330
DOI: 10.1038/s41586-022-05366-w