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Annual Review of Cell and Developmental... Oct 2020Many fundamental cellular processes such as division, polarization, endocytosis, and motility require the assembly, maintenance, and disassembly of filamentous actin... (Review)
Review
Many fundamental cellular processes such as division, polarization, endocytosis, and motility require the assembly, maintenance, and disassembly of filamentous actin (F-actin) networks at specific locations and times within the cell. The particular function of each network is governed by F-actin organization, size, and density as well as by its dynamics. The distinct characteristics of different F-actin networks are determined through the coordinated actions of specific sets of actin-binding proteins (ABPs). Furthermore, a cell typically assembles and uses multiple F-actin networks simultaneously within a common cytoplasm, so these networks must self-organize from a common pool of shared globular actin (G-actin) monomers and overlapping sets of ABPs. Recent advances in multicolor imaging and analysis of ABPs and their associated F-actin networks in cells, as well as the development of sophisticated in vitro reconstitutions of networks with ensembles of ABPs, have allowed the field to start uncovering the underlying principles by which cells self-organize diverse F-actin networks to execute basic cellular functions.
Topics: Actin Cytoskeleton; Actins; Animals; Humans; Microfilament Proteins; Models, Biological; Schizosaccharomyces
PubMed: 33021819
DOI: 10.1146/annurev-cellbio-032320-094706 -
Molecular and Cellular Biology Aug 2020Fodrin and its erythroid cell-specific isoform spectrin are actin-associated fibrous proteins that play crucial roles in the maintenance of structural integrity in... (Review)
Review
Fodrin and its erythroid cell-specific isoform spectrin are actin-associated fibrous proteins that play crucial roles in the maintenance of structural integrity in mammalian cells, which is necessary for proper cell function. Normal cell morphology is altered in diseases such as various cancers and certain neuronal disorders. Fodrin and spectrin are two-chain (αβ) molecules that are encoded by paralogous genes and share many features but also demonstrate certain differences. Fodrin (in humans, typically a heterodimer of the products of the SPTAN1 and SPTBN1 genes) is expressed in nearly all cell types and is especially abundant in neuronal tissues, whereas spectrin (in humans, a heterodimer of the products of the SPTA1 and SPTB1 genes) is expressed almost exclusively in erythrocytes. To fulfill a role in such a variety of different cell types, it was anticipated that fodrin would need to be a more versatile scaffold than spectrin. Indeed, as summarized here, domains unique to fodrin and its regulation by Ca, calmodulin, and a variety of posttranslational modifications (PTMs) endow fodrin with additional specific functions. However, how fodrin structural variations and misregulated PTMs may contribute to the etiology of various cancers and neurodegenerative diseases needs to be further investigated.
Topics: Actins; Animals; Calcium; Calmodulin; Carrier Proteins; Erythroid Cells; Humans; Microfilament Proteins; Neurons; Spectrin; Structure-Activity Relationship
PubMed: 32601107
DOI: 10.1128/MCB.00133-20 -
Genes Apr 2023Coronin proteins are actin-related proteins containing WD repeat domains encoded by seven genes (, , , , , , and ) in the human genome. Analysis of large cohort data...
Coronin proteins are actin-related proteins containing WD repeat domains encoded by seven genes (, , , , , , and ) in the human genome. Analysis of large cohort data from The Cancer Genome Atlas revealed that expression of , , , , and was significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) tissues ( < 0.05). Moreover, high expression of and significantly predicted the 5 year survival rate of patients with PDAC ( = 0.0071 and = 0.0389, respectively). In this study, we focused on and investigated its functional significance and epigenetic regulation in PDAC cells. Knockdown assays using siRNAs targeting were performed in PDAC cells. Aggressive cancer cell phenotypes, especially cancer cell migration and invasion, were inhibited by knockdown. The involvement of microRNAs (miRNAs) is a molecular mechanism underlying the aberrant expression of cancer-related genes in cancer cells. Our analysis revealed that five miRNAs (, , , , and ) are putative candidate miRNAs regulating expression in PDAC cells. Importantly, all five miRNAs exhibited tumor-suppressive functions and four miRNAs except negatively regulated expression in PDAC cells. and its downstream signaling molecules are potential therapeutic targets in PDAC.
Topics: Humans; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Epigenesis, Genetic; Microfilament Proteins; MicroRNAs; Pancreatic Neoplasms
PubMed: 37239355
DOI: 10.3390/genes14050995 -
Trends in Biochemical Sciences Jun 2016Two types of sequences, proline-rich domains (PRDs) and the WASP-homology 2 (WH2) domain, are found in most actin filament nucleation and elongation factors discovered... (Review)
Review
Two types of sequences, proline-rich domains (PRDs) and the WASP-homology 2 (WH2) domain, are found in most actin filament nucleation and elongation factors discovered thus far. PRDs serve as a platform for protein-protein interactions, often mediating the binding of profilin-actin. The WH2 domain is an abundant actin monomer-binding motif comprising ∼17 amino acids. It frequently occurs in tandem repeats, and functions in nucleation by recruiting actin subunits to form the polymerization nucleus. It is found in Spire, Cordon Bleu (Cobl), Leiomodin (Lmod), Arp2/3 complex activators (WASP, WHAMM, WAVE, etc.), the bacterial nucleators VopL/VopF and Sca2, and some formins. Yet, it is argued here that the WH2 domain plays only an auxiliary role in nucleation, always synergizing with other domains or proteins for this activity.
Topics: Actin Cytoskeleton; Actin-Related Protein 2-3 Complex; Actins; Amino Acid Sequence; Animals; Autoantigens; Bacteria; Cell Nucleus; Cytoskeletal Proteins; Drosophila melanogaster; Fetal Proteins; Formins; Humans; Microfilament Proteins; Nuclear Proteins; Polymerization; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Sequence Alignment; Sequence Homology, Amino Acid
PubMed: 27068179
DOI: 10.1016/j.tibs.2016.03.004 -
Seminars in Cell & Developmental Biology Sep 2017Microtubule-actin crosslinking factor 1 (MACF1), also known as actin crosslinking factor 7 (ACF7), is essential for proper modulation of actin and microtubule... (Review)
Review
Microtubule-actin crosslinking factor 1 (MACF1), also known as actin crosslinking factor 7 (ACF7), is essential for proper modulation of actin and microtubule cytoskeletal networks. Most MACF1 isoforms are expressed broadly in the body, but some are exclusively found in the nervous system. Consequentially, MACF1 is integrally involved in multiple neural processes during development and in adulthood, including neurite outgrowth and neuronal migration. Furthermore, MACF1 participates in several signaling pathways, including the Wnt/β-catenin and GSK-3 signaling pathways, which regulate key cellular processes, such as proliferation and cell migration. Genetic mutation or dysregulation of the MACF1 gene has been associated with neurodevelopmental and neurodegenerative diseases, specifically schizophrenia and Parkinson's disease. MACF1 may also play a part in neuromuscular disorders and have a neuroprotective role in the optic nerve. In this review, the authors seek to synthesize recent findings relating to the roles of MACF1 within the nervous system and explore potential novel functions of MACF1 not yet examined.
Topics: Animals; Cell Movement; Humans; Microfilament Proteins; Nervous System; Nervous System Diseases; Neurites; Signal Transduction
PubMed: 28579452
DOI: 10.1016/j.semcdb.2017.05.020 -
International Journal of Molecular... Jan 2018Plakins are a family of seven cytoskeletal cross-linker proteins (microtubule-actin crosslinking factor 1 (MACF), bullous pemphigoid antigen (BPAG1) desmoplakin,... (Review)
Review
Plakins are a family of seven cytoskeletal cross-linker proteins (microtubule-actin crosslinking factor 1 (MACF), bullous pemphigoid antigen (BPAG1) desmoplakin, envoplakin, periplakin, plectin, epiplakin) that network the three major filaments that comprise the cytoskeleton. Plakins have been found to be involved in disorders and diseases of the skin, heart, nervous system, and cancer that are attributed to autoimmune responses and genetic alterations of these macromolecules. Despite their role and involvement across a spectrum of several diseases, there are no current drugs or pharmacological agents that specifically target the members of this protein family. On the contrary, microtubules have traditionally been targeted by microtubule inhibiting agents, used for the treatment of diseases such as cancer, in spite of the deleterious toxicities associated with their clinical utility. The Research Collaboratory for Structural Bioinformatics (RCSB) was used here to identify therapeutic drugs targeting the plakin proteins, particularly the spectraplakins MACF1 and BPAG1, which contain microtubule-binding domains. RCSB analysis revealed that plakin proteins had 329 ligands, of which more than 50% were MACF1 and BPAG1 ligands and 10 were documented, clinically or experimentally, to have several therapeutic applications as anticancer, anti-inflammatory, and antibiotic agents.
Topics: Animals; Antineoplastic Agents; Binding Sites; Humans; Microfilament Proteins; Mitosis Modulators; Plakins; Protein Binding
PubMed: 29373494
DOI: 10.3390/ijms19020368 -
European Journal of Cell Biology 2022Actin is among the most abundant proteins in eukaryotic cells and assembles into dynamic filamentous networks regulated by many actin binding proteins. The actin... (Review)
Review
Actin is among the most abundant proteins in eukaryotic cells and assembles into dynamic filamentous networks regulated by many actin binding proteins. The actin cytoskeleton must be finely tuned, both in space and time, to fulfill key cellular functions such as cell division, cell shape changes, phagocytosis and cell migration. While actin oxidation by reactive oxygen species (ROS) at non-physiological levels are known for long to impact on actin polymerization and on the cellular actin cytoskeleton, growing evidence shows that direct and reversible oxidation/reduction of specific actin amino acids plays an important and physiological role in regulating the actin cytoskeleton. In this review, we describe which actin amino acid residues can be selectively oxidized and reduced in many different ways (e.g. disulfide bond formation, glutathionylation, carbonylation, nitration, nitrosylation and other oxidations), the cellular enzymes at the origin of these post-translational modifications, and the impact of actin redox modifications both in vitro and in vivo. We show that the regulated balance of oxidation and reduction of key actin amino acid residues contributes to the control of actin filament polymerization and disassembly at the subcellular scale and highlight how improper redox modifications of actin can lead to pathological conditions.
Topics: Actin Cytoskeleton; Actins; Amino Acids; Microfilament Proteins; Oxidation-Reduction
PubMed: 35716426
DOI: 10.1016/j.ejcb.2022.151249 -
Organization and dynamics of the actin cytoskeleton during dendritic spine morphological remodeling.Cellular and Molecular Life Sciences :... Aug 2016In the central nervous system, most excitatory post-synapses are small subcellular structures called dendritic spines. Their structure and morphological remodeling are... (Review)
Review
In the central nervous system, most excitatory post-synapses are small subcellular structures called dendritic spines. Their structure and morphological remodeling are tightly coupled to changes in synaptic transmission. The F-actin cytoskeleton is the main driving force of dendritic spine remodeling and sustains synaptic plasticity. It is therefore essential to understand how changes in synaptic transmission can regulate the organization and dynamics of actin binding proteins (ABPs). In this review, we will provide a detailed description of the organization and dynamics of F-actin and ABPs in dendritic spines and will discuss the current models explaining how the actin cytoskeleton sustains both structural and functional synaptic plasticity.
Topics: Actin Cytoskeleton; Actins; Animals; Dendritic Spines; Humans; Microfilament Proteins; Neuronal Plasticity; Signal Transduction; Synapses
PubMed: 27105623
DOI: 10.1007/s00018-016-2214-1 -
International Journal of Molecular... Dec 2021Glioblastoma (GBM) is the most common adult neural malignancy and the deadliest. The standard of care is optimal, safe, cytoreductive surgery followed by combined... (Review)
Review
Glioblastoma (GBM) is the most common adult neural malignancy and the deadliest. The standard of care is optimal, safe, cytoreductive surgery followed by combined radiation therapy and alkylating chemotherapy with temozolomide. Recurrence is common and therapeutic options in the recurrent setting are limited. The dismal prognosis of GBM has led to novel treatments being a serious roadblock in the field, with most new treatments failing to show efficacy. Targeted therapies have shown some success in many cancers, but GBM remains one of the most difficult to treat, especially in recurrence. New chemotherapeutic directions need to be explored, possibly expanding the targeted chemotherapy spectrum in previously unforeseen ways. In this perspective paper, we will explain why AVIL, an actin-binding protein recently found to be overexpressed in GBM and a driving force for GBM, could prove versatile in the fight against cancer. By looking at AVIL and its potential to regulate FOXM1 and LIN28B, we will be able to highlight a way to improve outcomes for GBM patients who normally have very little hope.
Topics: Cytoskeleton; Forkhead Box Protein M1; Glioblastoma; Humans; Microfilament Proteins; RNA-Binding Proteins
PubMed: 34948433
DOI: 10.3390/ijms222413635 -
Molecules (Basel, Switzerland) Apr 2021( co-regulated gene) shares a bi-directional promoter with the Parkinson's disease-associated gene , but the physiological roles of PACRG have not yet been fully...
( co-regulated gene) shares a bi-directional promoter with the Parkinson's disease-associated gene , but the physiological roles of PACRG have not yet been fully elucidated. Recombinant expression methods are indispensable for protein structural and functional studies. In this study, the coding region of was cloned to a conventional vector pQE80L, as well as two cold-shock vectors pCold II and pCold-GST, respectively. The constructs were transformed into (DE3), and the target proteins were overexpressed. The results showed that the cold-shock vectors are more suitable for PACRG expression. The soluble recombinant proteins were purified with Ni chelating column, glutathione S-transferase (GST) affinity chromatography and gel filtration. His pull down assay and LC-MS/MS were carried out for identification of PACRG-binding proteins in HEK293T cell lysates, and a total number of 74 proteins were identified as potential interaction partners of PACRG. GO (Gene ontology) enrichment analysis (FunRich) of the 74 proteins revealed multiple molecular functions and biological processes. The highest proportion of the 74 proteins functioned as transcription regulator and transcription factor activity, suggesting that PACRG may play important roles in regulation of gene transcription.
Topics: Chromatography, Affinity; Chromatography, Gel; Glutathione Transferase; HEK293 Cells; Humans; Microfilament Proteins; Molecular Chaperones; Protein Binding; Tandem Mass Spectrometry; Ubiquitin-Protein Ligases
PubMed: 33923444
DOI: 10.3390/molecules26082308