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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 -
Methods in Molecular Biology (Clifton,... 2023The actin cytoskeleton is a highly dynamic network in plant cells, which is precisely regulated by numerous actin-binding proteins. Hence, characterizing the biochemical...
The actin cytoskeleton is a highly dynamic network in plant cells, which is precisely regulated by numerous actin-binding proteins. Hence, characterizing the biochemical activities of actin-binding proteins is of great importance. Here we describe methods for determining the binding and bundling of microfilaments as well as methods for visualizing microfilaments using fluorescent phalloidin and single-molecule TIRF imaging.
Topics: Actins; Actin Cytoskeleton; Microfilament Proteins; Coloring Agents; Phalloidine
PubMed: 36773222
DOI: 10.1007/978-1-0716-2867-6_2 -
Proceedings of the National Academy of... Sep 2023Cellular form and function are controlled by the assembly and stability of actin cytoskeletal structures-but disassembling/pruning these structures is equally essential...
Cellular form and function are controlled by the assembly and stability of actin cytoskeletal structures-but disassembling/pruning these structures is equally essential for the plasticity and remodeling that underlie behavioral adaptations. Importantly, the mechanisms of actin assembly have been well-defined-including that it is driven by actin's polymerization into filaments (F-actin) and then often bundling by crosslinking proteins into stable higher-order structures. In contrast, it remains less clear how these stable bundled F-actin structures are rapidly disassembled. We now uncover mechanisms that rapidly and extensively disassemble bundled F-actin. Using biochemical, structural, and imaging assays with purified proteins, we show that F-actin bundled with one of the most prominent crosslinkers, fascin, is extensively disassembled by Mical, the F-actin disassembly enzyme. Furthermore, the product of this Mical effect, Mical-oxidized actin, is poorly bundled by fascin, thereby further amplifying Mical's disassembly effects on bundled F-actin. Moreover, another critical F-actin regulator, cofilin, also affects fascin-bundled filaments, but we find herein that it synergizes with Mical to dramatically amplify its disassembly of bundled F-actin compared to the sum of their individual effects. Genetic and high-resolution cellular assays reveal that Mical also counteracts crosslinking proteins/bundled F-actin in vivo to control cellular extension, axon guidance, and Semaphorin/Plexin cell-cell repulsion. Yet, our results also support the idea that fascin-bundling serves to dampen Mical's F-actin disassembly in vitro and in vivo-and that physiologically relevant cellular remodeling requires a fine-tuned interplay between the factors that build bundled F-actin networks and those that disassemble them.
Topics: Actins; Actin Depolymerizing Factors; Actin Cytoskeleton; Cytoskeleton; Axon Guidance
PubMed: 37725655
DOI: 10.1073/pnas.2309955120 -
Current Protein & Peptide Science 2023Thymosin β4 (Tβ4) is the β-thymosin (Tβs) with the highest expression level in human cells; it makes up roughly 70-80% of all Tβs in the human body. Combining the... (Review)
Review
Thymosin β4 (Tβ4) is the β-thymosin (Tβs) with the highest expression level in human cells; it makes up roughly 70-80% of all Tβs in the human body. Combining the mechanism and activity studies of Tβ4 in recent years, we provide an overview of the subtle molecular mechanism, pharmacological action, and clinical applications of Tβ4. As a G-actin isolator, Tβ4 inhibits the polymerization of G-actin by binding to the matching site of G-actin in a 1:1 ratio through conformational and spatial effects. Tβ4 can control the threshold concentration of G-actin in the cytoplasm, influence the balance of depolymerization and polymerization of F-actin (also called Tread Milling of F-actin), and subsequently affect cell's various physiological activities, especially motility, development and differentiation. Based on this, Tβ4 is known to have a wide range of effects, including regulation of inflammation and tumor metastasis, promotion of angiogenesis, wound healing, regeneration of hair follicles, promotion of the development of the nervous system, and improving bone formation and tooth growth. Tβ4 therefore has extensive medicinal applications in many fields, and serves to preserve the kidney, liver, heart, brain, intestine, and other organs, as well as hair loss, skin trauma, cornea repairing, and other conditions. In this review, we focus on the mechanism of action and clinical application of Tβ4 for its main biological functions.
Topics: Humans; Actins; Actin Cytoskeleton; Thymosin; Wound Healing
PubMed: 36464872
DOI: 10.2174/1389203724666221201093500 -
Journal of Cell Science May 2022Primary cilia play a key role in the ability of cells to respond to extracellular stimuli, such as signaling molecules and environmental cues. These sensory organelles... (Review)
Review
Primary cilia play a key role in the ability of cells to respond to extracellular stimuli, such as signaling molecules and environmental cues. These sensory organelles are crucial to the development of many organ systems, and defects in primary ciliogenesis lead to multisystemic genetic disorders, known as ciliopathies. Here, we review recent advances in the understanding of several key aspects of the regulation of ciliogenesis. Primary ciliogenesis is thought to take different pathways depending on cell type, and some recent studies shed new light on the cell-type-specific mechanisms regulating ciliogenesis at the apical surface in polarized epithelial cells, which are particularly relevant for many ciliopathies. Furthermore, recent findings have demonstrated the importance of actin cytoskeleton dynamics in positively and negatively regulating multiple stages of ciliogenesis, including the vesicular trafficking of ciliary components and the positioning and docking of the basal body. Finally, studies on the formation of motile cilia in multiciliated epithelial cells have revealed requirements for actin remodeling in this process too, as well as showing evidence of an additional alternative ciliogenesis pathway.
Topics: Actin Cytoskeleton; Actins; Basal Bodies; Cilia; Ciliopathies; Humans
PubMed: 35575063
DOI: 10.1242/jcs.259030 -
Biomolecules Aug 2023The eukaryotic actin cytoskeleton comprises the protein itself in its monomeric and filamentous forms, G- and F-actin, as well as multiple interaction partners... (Review)
Review
The eukaryotic actin cytoskeleton comprises the protein itself in its monomeric and filamentous forms, G- and F-actin, as well as multiple interaction partners (actin-binding proteins, ABPs). This gives rise to a temporally and spatially controlled, dynamic network, eliciting a plethora of motility-associated processes. To interfere with the complex inter- and intracellular interactions the actin cytoskeleton confers, small molecular inhibitors have been used, foremost of all to study the relevance of actin filaments and their turnover for various cellular processes. The most prominent inhibitors act by, e.g., sequestering monomers or by interfering with the polymerization of new filaments and the elongation of existing filaments. Among these inhibitors used as tool compounds are the cytochalasans, fungal secondary metabolites known for decades and exploited for their F-actin polymerization inhibitory capabilities. In spite of their application as tool compounds for decades, comprehensive data are lacking that explain (i) how the structural deviances of the more than 400 cytochalasans described to date influence their bioactivity mechanistically and (ii) how the intricate network of ABPs reacts (or adapts) to cytochalasan binding. This review thus aims to summarize the information available concerning the structural features of cytochalasans and their influence on the described activities on cell morphology and actin cytoskeleton organization in eukaryotic cells.
Topics: Actins; Actin Cytoskeleton; Cell Physiological Phenomena; Cytoskeleton; Cytochalasins
PubMed: 37627312
DOI: 10.3390/biom13081247 -
Cytoskeleton (Hoboken, N.J.) Jun 2021The actin cytoskeleton is important for maintaining mechanical homeostasis in adherent cells, largely through its regulation of adhesion and cortical tension. The LIM... (Review)
Review
The actin cytoskeleton is important for maintaining mechanical homeostasis in adherent cells, largely through its regulation of adhesion and cortical tension. The LIM (Lin-11, Isl1, MEC-3) domain-containing proteins are involved in a myriad of cellular mechanosensitive pathways. Recent work has discovered that LIM domains bind to mechanically stressed actin filaments, suggesting a novel and widely conserved mechanism of mechanosensing. This review summarizes the current state of knowledge of LIM protein mechanosensitivity.
Topics: Actin Cytoskeleton; Actins; Biophysics; Cell Communication; LIM Domain Proteins; Protein Binding
PubMed: 34028199
DOI: 10.1002/cm.21677 -
F1000Research 2019Actin polymerization is essential for cells to migrate, as well as for various cell biological processes such as cytokinesis and vesicle traffic. This brief review... (Review)
Review
Actin polymerization is essential for cells to migrate, as well as for various cell biological processes such as cytokinesis and vesicle traffic. This brief review describes the mechanisms underlying its different roles and recent advances in our understanding. Actin usually requires "nuclei"-preformed actin filaments-to start polymerizing, but, once initiated, polymerization continues constitutively. The field therefore has a strong focus on nucleators, in particular the Arp2/3 complex and formins. These have different functions, are controlled by contrasting mechanisms, and generate alternate geometries of actin networks. The Arp2/3 complex functions only when activated by nucleation-promoting factors such as WASP, Scar/WAVE, WASH, and WHAMM and when binding to a pre-existing filament. Formins can be individually active but are usually autoinhibited. Each is controlled by different mechanisms and is involved in different biological roles. We also describe the processes leading to actin disassembly and their regulation and conclude with four questions whose answers are important for understanding actin dynamics but are currently unanswered.
Topics: Actin Cytoskeleton; Actin-Related Protein 2-3 Complex; Actins; Cell Movement; Cytoskeleton
PubMed: 31824651
DOI: 10.12688/f1000research.18669.1 -
Current Opinion in Cell Biology Feb 2021An intimate interplay of the plasma membrane with curvature-sensing and curvature-inducing proteins would allow for defining specific sites or nanodomains of action at... (Review)
Review
An intimate interplay of the plasma membrane with curvature-sensing and curvature-inducing proteins would allow for defining specific sites or nanodomains of action at the plasma membrane, for example, for protrusion, invagination, and polarization. In addition, such connections are predestined to ensure spatial and temporal order and sequences. The combined forces of membrane shapers and the cortical actin cytoskeleton might hereby in particular be required to overcome the strong resistance against membrane rearrangements in case of high plasma membrane tension or cellular turgor. Interestingly, also the opposite might be necessary, the inhibition of both membrane shapers and cytoskeletal reinforcement structures to relieve membrane tension to protect cells from membrane damage and rupturing during mechanical stress. In this review article, we discuss recent conceptual advances enlightening the interplay of plasma membrane curvature and the cortical actin cytoskeleton during endocytosis, modulations of membrane tensions, and the shaping of entire cells.
Topics: Actin Cytoskeleton; Actins; Animals; Cell Membrane; Cell Shape; Cytoskeleton; Endocytosis; Humans; Yeasts
PubMed: 32927373
DOI: 10.1016/j.ceb.2020.08.008 -
Current Opinion in Cell Biology Feb 2023How cells move is a fundamental biological question. The directionality of adherent migrating cells depends on the assembly and disassembly (turnover) of focal adhesions... (Review)
Review
How cells move is a fundamental biological question. The directionality of adherent migrating cells depends on the assembly and disassembly (turnover) of focal adhesions (FAs). FAs are micron-sized actin-based structures that link cells to the extracellular matrix. Traditionally, microtubules have been considered key to triggering FA turnover. Through the years, advancements in biochemistry, biophysics, and bioimaging tools have been invaluable for many research groups to unravel a variety of mechanisms and molecular players that contribute to FA turnover, beyond microtubules. Here, we discuss recent discoveries of key molecular players that affect the dynamics and organization of the actin cytoskeleton to enable timely FA turnover and consequently proper directed cell migration.
Topics: Focal Adhesions; Actins; Cell Movement; Microtubules; Actin Cytoskeleton; Cell Adhesion
PubMed: 36796142
DOI: 10.1016/j.ceb.2023.102152