-
Nature Reviews. Molecular Cell Biology Oct 2014Capping protein (CP) binds the fast growing barbed end of the actin filament and regulates actin assembly by blocking the addition and loss of actin subunits. Recent... (Review)
Review
Capping protein (CP) binds the fast growing barbed end of the actin filament and regulates actin assembly by blocking the addition and loss of actin subunits. Recent studies provide new insights into how CP and barbed-end capping are regulated. Filament elongation factors, such as formins and ENA/VASP (enabled/vasodilator-stimulated phosphoprotein), indirectly regulate CP by competing with CP for binding to the barbed end, whereas other molecules, including V-1 and phospholipids, directly bind to CP and sterically block its interaction with the filament. In addition, a diverse and unrelated group of proteins interact with CP through a conserved 'capping protein interaction' (CPI) motif. These proteins, including CARMIL (capping protein, ARP2/3 and myosin I linker), CD2AP (CD2-associated protein) and the WASH (WASP and SCAR homologue) complex subunit FAM21, recruit CP to specific subcellular locations and modulate its actin-capping activity via allosteric effects.
Topics: Actin Capping Proteins; Actin Cytoskeleton; Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Carrier Proteins; Cytoskeletal Proteins; DNA-Binding Proteins; Humans; Microfilament Proteins; Models, Molecular; Phosphatidylinositol Phosphates; Protein Binding; Protein Conformation
PubMed: 25207437
DOI: 10.1038/nrm3869 -
BMB Reports Jan 2016Spectraplakins are crucially important communicators, linking cytoskeletal components to each other and cellular junctions. Microtubule actin crosslinking factor 1... (Review)
Review
Spectraplakins are crucially important communicators, linking cytoskeletal components to each other and cellular junctions. Microtubule actin crosslinking factor 1 (MACF1), also known as actin crosslinking family 7 (ACF7), is a member of the spectraplakin family. It is expressed in numerous tissues and cells as one extensively studied spectraplakin. MACF1 has several isoforms with unique structures and well-known function to be able to crosslink F-actin and microtubules. MACF1 is one versatile spectraplakin with various functions in cell processes, embryo development, tissue-specific functions, and human diseases. The importance of MACF1 has become more apparent in recent years. Here, we summarize the current knowledge on the presence and function of MACF1 and provide perspectives on future research of MACF1 based on our studies and others.
Topics: Actins; Animals; Cell Movement; Embryo, Mammalian; Humans; Microfilament Proteins; Protein Binding; Protein Isoforms; Protein Structure, Tertiary; Signal Transduction
PubMed: 26521939
DOI: 10.5483/BMBRep.2016.49.1.185 -
Trends in Biochemical Sciences Oct 2019Transgelin-2 has been regarded as an actin-binding protein that induces actin gelation and regulates actin cytoskeleton. However, transgelin-2 has recently been shown to... (Review)
Review
Transgelin-2 has been regarded as an actin-binding protein that induces actin gelation and regulates actin cytoskeleton. However, transgelin-2 has recently been shown to relax the myosin cytoskeleton of the airway smooth muscle cells by acting as a receptor for extracellular metallothionein-2. From a clinical perspective, these results support transgelin-2 as a promising therapeutic target for diseases such as cancer and asthma. The inhibition of transgelin-2 prevents actin gelation and thereby cancer cell proliferation, invasion, and metastasis. Conversely, the activation of transgelin-2 with specific agonists relaxes airway smooth muscles and reduces pulmonary resistance in asthma. Here, we review new studies on the biochemical properties of transgelin-2 and discuss their clinical implications for the treatment of immune, oncogenic, and respiratory disorders.
Topics: Actins; Animals; Asthma; Cell Proliferation; Humans; Microfilament Proteins; Muscle Proteins; Neoplasms
PubMed: 31256982
DOI: 10.1016/j.tibs.2019.05.004 -
Science Translational Medicine Feb 2018There is a clinical need for new bronchodilator drugs in asthma, because more than half of asthmatic patients do not receive adequate control with current available...
There is a clinical need for new bronchodilator drugs in asthma, because more than half of asthmatic patients do not receive adequate control with current available treatments. We report that inhibition of metallothionein-2 protein expression in lung tissues causes the increase of pulmonary resistance. Conversely, metallothionein-2 protein is more effective than β-agonists in reducing pulmonary resistance in rodent asthma models, alleviating tension in tracheal spirals, and relaxing airway smooth muscle cells (ASMCs). Metallothionein-2 relaxes ASMCs via transgelin-2 (TG2) and induces dephosphorylation of myosin phosphatase target subunit 1 (MYPT1). We identify TSG12 as a nontoxic, specific TG2-agonist that relaxes ASMCs and reduces asthmatic pulmonary resistance. In vivo, TSG12 reduces pulmonary resistance in both ovalbumin- and house dust mite-induced asthma in mice. TSG12 induces RhoA phosphorylation, thereby inactivating the RhoA-ROCK-MYPT1-MLC pathway and causing ASMCs relaxation. TSG12 is more effective than β-agonists in relaxing human ASMCs and pulmonary resistance with potential clinical advantages. These results suggest that TSG12 could be a promising therapeutic approach for treating asthma.
Topics: Animals; Asthma; Disease Models, Animal; Lung; Mice; Mice, Knockout; Microfilament Proteins; Molecular Docking Simulation; Muscle Proteins
PubMed: 29437149
DOI: 10.1126/scitranslmed.aam8604 -
Cell Proliferation Jan 2021Members of the growth arrest-specific 2 (GAS2) protein family consist of a putative actin-binding (CH) domain and a microtubule-binding (GAR) domain and are considered... (Review)
Review
Members of the growth arrest-specific 2 (GAS2) protein family consist of a putative actin-binding (CH) domain and a microtubule-binding (GAR) domain and are considered miniversions of spectraplakins. There are four members in the GAS2 family, viz. GAS2, GAS2L1, GAS2L2 and GAS2L3. Although GAS2 is defined as a family of growth arrest-specific proteins, the significant differences in the expression patterns, interaction characteristics and biological issues or diseases among the different GAS2 family members have not been systemically reviewed to date. Therefore, we summarized the available evidence on the structures and functions of GAS2 family members. This review facilitates a comprehensive molecular understanding of the involvement of the GAS2 family members in an array of biological processes, including cytoskeleton reorganization, cell cycle, apoptosis and cancer development.
Topics: Apoptosis; Cell Cycle; Cytoskeleton; Humans; Microfilament Proteins; Neoplasms
PubMed: 33103301
DOI: 10.1111/cpr.12934 -
Genome Biology and Evolution Jan 2020Ezrin, radixin, moesin, and merlin are cytoskeletal proteins, whose functions are specific to metazoans. They participate in cell cortex rearrangement, including...
Ezrin, radixin, moesin, and merlin are cytoskeletal proteins, whose functions are specific to metazoans. They participate in cell cortex rearrangement, including cell-cell contact formation, and play an important role in cancer progression. Here, we have performed a comprehensive phylogenetic analysis of the proteins spanning 87 species. The results describe a possible mechanism for the protein family origin in the root of Metazoa, paralogs diversification in vertebrates, and acquisition of novel functions, including tumor suppression. In addition, a merlin paralog, present in most vertebrates but lost in mammals, has been described here for the first time. We have also highlighted a set of amino acid variations within the conserved motifs as the candidates for determining physiological differences between ERM paralogs.
Topics: Amino Acid Motifs; Animals; Cytoskeletal Proteins; Evolution, Molecular; Fishes; Humans; Membrane Proteins; Microfilament Proteins; Multigene Family; Neurofibromin 2; Phylogeny; Synteny
PubMed: 31851361
DOI: 10.1093/gbe/evz265 -
Experimental Biology and Medicine... Nov 2019The cytoskeleton is an essential element of a eukaryotic cell which informs both form and function and ultimately has physiological consequences for the organism.... (Review)
Review
UNLABELLED
The cytoskeleton is an essential element of a eukaryotic cell which informs both form and function and ultimately has physiological consequences for the organism. Equally as important as the major cytoskeletal networks are crosslinkers which coordinate and regulate their activities. One such category of crosslinker is the spectraplakins, a family of giant, evolutionarily conserved crosslinking proteins with the rare ability to interact with each of the three major cytoskeletal networks. In particular, a mammalian spectraplakin isotype called MACF1 (microtubule actin crosslinking factor 1), also known as ACF7 (actin crosslinking factor 7), has been of particular interest in the years since its discovery; MACF1 has come under such scrutiny due to the mounting list of biological phenomena in which it has been implicated. This review is an overview of the current knowledge on the structure and function of the known spectraplakin isotypes with an emphasis on MACF1, recent studies on MACF1, and finally, an analysis of the potential of MACF1 to advance medicine.
IMPACT STATEMENT
Spectraplakins are a highly conserved group of proteins which have the rare ability to bind to each of the three major cytoskeletal networks. The mammalian spectraplakin MACF1/ACF7 has proven to be instrumental in many cellular processes (e.g. signaling and cell migration) since its identification and, as such, has been the focus of various research studies. This review is a synthesis of scientific reports on the structure, confirmed functions, and implicated roles of MACF1/ACF7 as of 2019. Based on what has been revealed thus far in terms of MACF1/ACF7’s role in complex pathologies such as metastatic cancers and inflammatory bowel disease, it appears that MACF1/ACF7 and the continued study thereof hold great potential to both enhance the design of future therapies for various diseases and vastly expand scientific understanding of organismal physiology as a whole.
Topics: Animals; Cytoskeleton; Humans; Microfilament Proteins
PubMed: 31398993
DOI: 10.1177/1535370219864920 -
Anillin forms linear structures and facilitates furrow ingression after septin and formin depletion.Cell Reports Sep 2023During cytokinesis, a contractile ring consisting of unbranched filamentous actin (F-actin) and myosin II constricts at the cell equator. Unbranched F-actin is generated...
During cytokinesis, a contractile ring consisting of unbranched filamentous actin (F-actin) and myosin II constricts at the cell equator. Unbranched F-actin is generated by formin, and without formin no cleavage furrow forms. In Caenorhabditis elegans, depletion of septin restores furrow ingression in formin mutants. How the cleavage furrow ingresses without a detectable unbranched F-actin ring is unknown. We report that, in this setting, anillin (ANI-1) forms a meshwork of circumferentially aligned linear structures decorated by non-muscle myosin II (NMY-2). Analysis of ANI-1 deletion mutants reveals that its disordered N-terminal half is required for linear structure formation and sufficient for furrow ingression. NMY-2 promotes the circumferential alignment of the linear ANI-1 structures and interacts with various lipids, suggesting that NMY-2 links the ANI-1 network with the plasma membrane. Collectively, our data reveal a compensatory mechanism, mediated by ANI-1 linear structures and membrane-bound NMY-2, that promotes furrowing when unbranched F-actin polymerization is compromised.
Topics: Animals; Actins; Septins; Formins; Cytokinesis; Cell Membrane; Caenorhabditis elegans; Myosin Type II; Microfilament Proteins; Caenorhabditis elegans Proteins; Contractile Proteins
PubMed: 37665665
DOI: 10.1016/j.celrep.2023.113076 -
International Journal of Molecular... Apr 2019The merlin-ERM (ezrin, radixin, moesin) family of proteins plays a central role in linking the cellular membranes to the cortical actin cytoskeleton. Merlin regulates... (Review)
Review
The merlin-ERM (ezrin, radixin, moesin) family of proteins plays a central role in linking the cellular membranes to the cortical actin cytoskeleton. Merlin regulates contact inhibition and is an integral part of cell-cell junctions, while ERM proteins, ezrin, radixin and moesin, assist in the formation and maintenance of specialized plasma membrane structures and membrane vesicle structures. These two protein families share a common evolutionary history, having arisen and separated via gene duplication near the origin of metazoa. During approximately 0.5 billion years of evolution, the merlin and ERM family proteins have maintained both sequence and structural conservation to an extraordinary level. Comparing crystal structures of merlin-ERM proteins and their complexes, a picture emerges of the merlin-ERM proteins acting as switchable interaction hubs, assembling protein complexes on cellular membranes and linking them to the actin cytoskeleton. Given the high level of structural conservation between the merlin and ERM family proteins we speculate that they may function together.
Topics: Actin Cytoskeleton; Amino Acid Sequence; Animals; Cell Membrane; Contact Inhibition; Cytoskeletal Proteins; Humans; Membrane Proteins; Microfilament Proteins; Models, Molecular; Neurofibromin 2; Protein Conformation; Protein Domains; Protein Interaction Maps; Sequence Alignment
PubMed: 31018575
DOI: 10.3390/ijms20081996 -
Cellular and Molecular Life Sciences :... Sep 2018The acetylation of the lysine 40 residue of α-tubulin was described more than 30 years ago and has been the subject of intense research ever since. Although the exact... (Review)
Review
The acetylation of the lysine 40 residue of α-tubulin was described more than 30 years ago and has been the subject of intense research ever since. Although the exact function of this covalent modification of tubulin in the cell remains unknown, it has been established that tubulin acetylation confers resilience to mechanical stress on the microtubules. Formins have a dual role in the fate of the actin and tubulin cytoskeletons. On the one hand, they catalyze the formation of actin filaments, and on the other, they bind microtubules, act on their stability, and regulate their acetylation and alignment with actin fibers. Recent evidence indicates that formins coordinate the actin cytoskeleton and tubulin acetylation by modulating the levels of free globular actin (G-actin). G-actin, in turn, controls the activity of the myocardin-related transcription factor-serum response factor transcriptional complex that regulates the expression of the α-tubulin acetyltransferase 1 (α-TAT1) gene, which encodes the main enzyme responsible for tubulin acetylation. The effect of formins on tubulin acetylation is the combined result of their ability to activate α-TAT1 gene transcription and of their capacity to regulate microtubule stabilization. The contribution of these two mechanisms in different formins is discussed, particularly with respect to INF2, a formin that is mutated in hereditary human renal and neurodegenerative disorders.
Topics: Acetylation; Actin Cytoskeleton; Formins; Humans; Kidney Diseases; Microfilament Proteins; Microtubules; Models, Biological; Mutation; Neurodegenerative Diseases; Protein Binding
PubMed: 29947928
DOI: 10.1007/s00018-018-2855-3