-
Cells Apr 2019The cytoskeleton of animal cells is one of the most complicated and functionally versatile structures, involved in processes such as endocytosis, cell division,... (Review)
Review
The cytoskeleton of animal cells is one of the most complicated and functionally versatile structures, involved in processes such as endocytosis, cell division, intra-cellular transport, motility, force transmission, reaction to external forces, adhesion and preservation, and adaptation of cell shape. These functions are mediated by three classical cytoskeletal filament types, as follows: Actin, microtubules, and intermediate filaments. The named filaments form a network that is highly structured and dynamic, responding to external and internal cues with a quick reorganization that is orchestrated on the time scale of minutes and has to be tightly regulated. Especially in brain tumors, the cytoskeleton plays an important role in spreading and migration of tumor cells. As the cytoskeletal organization and regulation is complex and many-faceted, this review aims to summarize the findings about cytoskeletal filament types, including substructures formed by them, such as lamellipodia, stress fibers, and interactions between intermediate filaments, microtubules and actin. Additionally, crucial regulatory aspects of the cytoskeletal filaments and the formed substructures are discussed and integrated into the concepts of cell motility. Even though little is known about the impact of cytoskeletal alterations on the progress of glioma, a final point discussed will be the impact of established cytoskeletal alterations in the cellular behavior and invasion of glioma.
Topics: Actins; Animals; Biological Transport; Cell Division; Cell Movement; Cell Shape; Cytoskeleton; Glioma; Humans; Intermediate Filaments; Microtubules; Signal Transduction
PubMed: 31003495
DOI: 10.3390/cells8040362 -
Seminars in Cancer Biology Nov 2022The cytoskeleton plays an integral role in maintaining the integrity of epithelial cells. Epithelial cells primarily employ cytokeratin in their cytoskeleton, whereas... (Review)
Review
The cytoskeleton plays an integral role in maintaining the integrity of epithelial cells. Epithelial cells primarily employ cytokeratin in their cytoskeleton, whereas mesenchymal cells use vimentin. During the epithelial-mesenchymal transition (EMT), cytokeratin-positive epithelial cells begin to express vimentin. EMT induces stem cell properties and drives metastasis, chemoresistance, and tumor relapse. Most studies of the functions of cytokeratin and vimentin have relied on the use of either epithelial or mesenchymal cell types. However, it is important to understand how these two cytoskeleton intermediate filaments function when co-expressed in cells undergoing EMT. Here, we discuss the individual and shared functions of cytokeratin and vimentin that coalesce during EMT and how alterations in intermediate filament expression influence carcinoma progression.
Topics: Humans; Intermediate Filaments; Keratins; Vimentin; Cytoskeleton; Epithelial-Mesenchymal Transition
PubMed: 34953942
DOI: 10.1016/j.semcancer.2021.12.006 -
Trends in Neurosciences Jun 2015Glial fibrillary acidic protein (GFAP) is an intermediate filament (IF) III protein uniquely found in astrocytes in the central nervous system (CNS), non-myelinating... (Review)
Review
Glial fibrillary acidic protein (GFAP) is an intermediate filament (IF) III protein uniquely found in astrocytes in the central nervous system (CNS), non-myelinating Schwann cells in the peripheral nervous system (PNS), and enteric glial cells. GFAP mRNA expression is regulated by several nuclear-receptor hormones, growth factors, and lipopolysaccharides (LPSs). GFAP is also subject to numerous post-translational modifications (PTMs), while GFAP mutations result in protein deposits known as Rosenthal fibers in Alexander disease. GFAP gene activation and protein induction appear to play a critical role in astroglial cell activation (astrogliosis) following CNS injuries and neurodegeneration. Emerging evidence also suggests that, following traumatic brain and spinal cord injuries and stroke, GFAP and its breakdown products are rapidly released into biofluids, making them strong candidate biomarkers for such neurological disorders.
Topics: Animals; Biomarkers; Glial Fibrillary Acidic Protein; Gliosis; Humans; Intermediate Filaments
PubMed: 25975510
DOI: 10.1016/j.tins.2015.04.003 -
Cold Spring Harbor Perspectives in... Apr 2017SUMMARYNeurofilaments (NFs) are unique among tissue-specific classes of intermediate filaments (IFs) in being heteropolymers composed of four subunits (NF-L... (Review)
Review
SUMMARYNeurofilaments (NFs) are unique among tissue-specific classes of intermediate filaments (IFs) in being heteropolymers composed of four subunits (NF-L [neurofilament light]; NF-M [neurofilament middle]; NF-H [neurofilament heavy]; and α-internexin or peripherin), each having different domain structures and functions. Here, we review how NFs provide structural support for the highly asymmetric geometries of neurons and, especially, for the marked radial expansion of myelinated axons crucial for effective nerve conduction velocity. NFs in axons extensively cross-bridge and interconnect with other non-IF components of the cytoskeleton, including microtubules, actin filaments, and other fibrous cytoskeletal elements, to establish a regionally specialized network that undergoes exceptionally slow local turnover and serves as a docking platform to organize other organelles and proteins. We also discuss how a small pool of oligomeric and short filamentous precursors in the slow phase of axonal transport maintains this network. A complex pattern of phosphorylation and dephosphorylation events on each subunit modulates filament assembly, turnover, and organization within the axonal cytoskeleton. Multiple factors, and especially turnover rate, determine the size of the network, which can vary substantially along the axon. NF gene mutations cause several neuroaxonal disorders characterized by disrupted subunit assembly and NF aggregation. Additional NF alterations are associated with varied neuropsychiatric disorders. New evidence that subunits of NFs exist within postsynaptic terminal boutons and influence neurotransmission suggests how NF proteins might contribute to normal synaptic function and neuropsychiatric disease states.
Topics: Animals; Biomarkers; Humans; Intermediate Filaments; Mental Disorders; Neurofilament Proteins; Organelles; Protein Processing, Post-Translational
PubMed: 28373358
DOI: 10.1101/cshperspect.a018309 -
ELife Apr 2022Mapping intermediate filaments in three dimensions reveals that the organization of these filaments differs across cell types.
Mapping intermediate filaments in three dimensions reveals that the organization of these filaments differs across cell types.
Topics: Cytoskeleton; Intermediate Filaments
PubMed: 35377313
DOI: 10.7554/eLife.78248 -
ASN Neuro 2020Fifty years have passed since the discovery of glial fibrillary acidic protein (GFAP) by Lawrence Eng and colleagues. Now recognized as a member of the intermediate... (Review)
Review
Fifty years have passed since the discovery of glial fibrillary acidic protein (GFAP) by Lawrence Eng and colleagues. Now recognized as a member of the intermediate filament family of proteins, it has become a subject for study in fields as diverse as structural biology, cell biology, gene expression, basic neuroscience, clinical genetics and gene therapy. This review covers each of these areas, presenting an overview of current understanding and controversies regarding GFAP with the goal of stimulating continued study of this fascinating protein.
Topics: Alexander Disease; Animals; Astrocytes; Cloning, Molecular; Glial Fibrillary Acidic Protein; Humans; Intermediate Filaments; Time Factors
PubMed: 32811163
DOI: 10.1177/1759091420949680 -
Methods in Enzymology 2016Keratins comprise the type I and type II intermediate filament-forming proteins and occur primarily in epithelial cells. They are encoded by 54 evolutionarily conserved...
Keratins comprise the type I and type II intermediate filament-forming proteins and occur primarily in epithelial cells. They are encoded by 54 evolutionarily conserved genes (28 type I, 26 type II) and regulated in a pairwise and tissue type-, differentiation-, and context-dependent manner. Keratins serve multiple homeostatic and stress-enhanced mechanical and nonmechanical functions in epithelia, including the maintenance of cellular integrity, regulation of cell growth and migration, and protection from apoptosis. These functions are tightly regulated by posttranslational modifications as well as keratin-associated proteins. Genetically determined alterations in keratin-coding sequences underlie highly penetrant and rare disorders whose pathophysiology reflects cell fragility and/or altered tissue homeostasis. Moreover, keratin mutation or misregulation represents risk factors or genetic modifiers for several acute and chronic diseases. This chapter focuses on keratins that are expressed in skin epithelia, and details a number of basic protocols and assays that have proven useful for analyses being carried out in skin.
Topics: Animals; Cells, Cultured; Humans; Intermediate Filaments; Keratinocytes; Keratins; Protein Processing, Post-Translational; Skin
PubMed: 26795476
DOI: 10.1016/bs.mie.2015.09.032 -
Cytoskeleton (Hoboken, N.J.) Apr 2021The cytoskeleton plays important roles in many essential processes at the cellular and organismal levels, including cell migration and motility, cell division, and the... (Review)
Review
The cytoskeleton plays important roles in many essential processes at the cellular and organismal levels, including cell migration and motility, cell division, and the establishment and maintenance of cell and tissue architecture. In order to facilitate these varied functions, the main cytoskeletal components-microtubules, actin filaments, and intermediate filaments-must form highly diverse intracellular arrays in different subcellular areas and cell types. The question of how this diversity is conferred has been the focus of research for decades. One key mechanism is the addition of posttranslational modifications (PTMs) to the major cytoskeletal proteins. This posttranslational addition of various chemical groups dramatically increases the complexity of the cytoskeletal proteome and helps facilitate major global and local cytoskeletal functions. Cytoskeletal proteins undergo many PTMs, most of which are not well understood. Recent technological advances in proteomics and cell biology have allowed for the in-depth study of individual PTMs and their functions in the cytoskeleton. Here, we provide an overview of the major PTMs that occur on the main structural components of the three cytoskeletal systems-tubulin, actin, and intermediate filament proteins-and highlight the cellular function of these modifications.
Topics: Cytoskeletal Proteins; Cytoskeleton; Intermediate Filaments; Microtubules; Protein Processing, Post-Translational
PubMed: 34152688
DOI: 10.1002/cm.21679 -
Current Opinion in Cell Biology Feb 2021Intermediate filaments (IFs) are key players in multiple cellular processes throughout human tissues. Their biochemical and structural properties are important for... (Review)
Review
Intermediate filaments (IFs) are key players in multiple cellular processes throughout human tissues. Their biochemical and structural properties are important for understanding filament assembly mechanisms, for interactions between IFs and binding partners, and for developing pharmacological agents that target IFs. IF proteins share a conserved coiled-coil central-rod domain flanked by variable N-terminal 'head' and C-terminal 'tail' domains. There have been several recent advances in our understanding of IF structure from the study of keratins, glial fibrillary acidic protein, and lamin. These include discoveries of (i) a knob-pocket tetramer assembly mechanism in coil 1B; (ii) a lamin-specific coil 1B insert providing a one-half superhelix turn; (iii) helical, yet flexible, linkers within the rod domain; and (iv) the identification of coil 2B residues required for mature filament assembly. Furthermore, the head and tail domains of some IFs contain low-complexity aromatic-rich kinked segments, and structures of IFs with binding partners show electrostatic surfaces are a major contributor to complex formation. These new data advance the connection between IF structure, pathologic mutations, and clinical diseases in humans.
Topics: Amino Acid Sequence; Animals; Cytoskeleton; Humans; Intermediate Filament Proteins; Intermediate Filaments; Lamins; Models, Molecular; Mutation
PubMed: 33190098
DOI: 10.1016/j.ceb.2020.10.001 -
Cells Sep 2021Given the role of intermediate filaments (IFs) in normal cell physiology and scores of IF-linked diseases, the importance of understanding their molecular structure is... (Review)
Review
Given the role of intermediate filaments (IFs) in normal cell physiology and scores of IF-linked diseases, the importance of understanding their molecular structure is beyond doubt. Research into the IF structure was initiated more than 30 years ago, and some important advances have been made. Using crystallography and other methods, the central coiled-coil domain of the elementary dimer and also the structural basis of the soluble tetramer formation have been studied to atomic precision. However, the molecular interactions driving later stages of the filament assembly are still not fully understood. For cytoplasmic IFs, much of the currently available insight is due to chemical cross-linking experiments that date back to the 1990s. This technique has since been radically improved, and several groups have utilized it recently to obtain data on lamin filament assembly. Here, we will summarize these findings and reflect on the remaining open questions and challenges of IF structure. We argue that, in addition to X-ray crystallography, chemical cross-linking and cryoelectron microscopy are the techniques that should enable major new advances in the field in the near future.
Topics: Animals; Cell Physiological Phenomena; Cytoskeleton; Humans; Intermediate Filaments
PubMed: 34572105
DOI: 10.3390/cells10092457