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Cells Jan 2022MCPH1, or BRIT1, is often mutated in human primary microcephaly type 1, a neurodevelopmental disorder characterized by a smaller brain size at birth, due to its... (Review)
Review
MCPH1, or BRIT1, is often mutated in human primary microcephaly type 1, a neurodevelopmental disorder characterized by a smaller brain size at birth, due to its dysfunction in regulating the proliferation and self-renewal of neuroprogenitor cells. In the last 20 years or so, genetic and cellular studies have identified MCPH1 as a multifaceted protein in various cellular functions, including DNA damage signaling and repair, the regulation of chromosome condensation, cell-cycle progression, centrosome activity and the metabolism. Yet, genetic and animal model studies have revealed an unpredicted essential function of MPCH1 in gonad development and tumorigenesis, although the underlying mechanism remains elusive. These studies have begun to shed light on the role of MPCH1 in controlling various pathobiological processes of the disorder. Here, we summarize the biological functions of MCPH1, and lessons learnt from cellular and mouse models of MCPH1.
Topics: Animals; Brain; Cytoskeletal Proteins; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Microcephaly; Neurogenesis
PubMed: 35053391
DOI: 10.3390/cells11020275 -
Biomolecules Feb 2024The protein 4.1R is an essential component of the erythrocyte membrane skeleton, serving as a key structural element and contributing to the regulation of the membrane's... (Review)
Review
The protein 4.1R is an essential component of the erythrocyte membrane skeleton, serving as a key structural element and contributing to the regulation of the membrane's physical properties, including mechanical stability and deformability, through its interaction with spectrin-actin. Recent research has uncovered additional roles of 4.1R beyond its function as a linker between the plasma membrane and the membrane skeleton. It has been found to play a crucial role in various biological processes, such as cell fate determination, cell cycle regulation, cell proliferation, and cell motility. Additionally, 4.1R has been implicated in cancer, with numerous studies demonstrating its potential as a diagnostic and prognostic biomarker for tumors. In this review, we provide an updated overview of the gene and protein structure of 4.1R, as well as its cellular functions in both physiological and pathological contexts.
Topics: Membrane Proteins; Cytoskeletal Proteins; Spectrin; Actins; Erythrocyte Membrane
PubMed: 38397451
DOI: 10.3390/biom14020214 -
Cells Jan 2022The most common clinical tachyarrhythmia, atrial fibrillation (AF), is present in 1-2% of the population. Although common risk factors, including hypertension, diabetes,... (Review)
Review
The most common clinical tachyarrhythmia, atrial fibrillation (AF), is present in 1-2% of the population. Although common risk factors, including hypertension, diabetes, and obesity, frequently underlie AF onset, it has been recognized that in 15% of the AF population, AF is familial. In these families, genome and exome sequencing techniques identified variants in the non-coding genome (i.e., variant regulatory elements), genes encoding ion channels, as well as genes encoding cytoskeletal (-associated) proteins. Cytoskeletal protein variants include variants in desmin, lamin A/C, titin, myosin heavy and light chain, junctophilin, nucleoporin, nesprin, and filamin C. These cytoskeletal protein variants have a strong association with the development of cardiomyopathy. Interestingly, AF onset is often represented as the initial manifestation of cardiac disease, sometimes even preceding cardiomyopathy by several years. Although emerging research findings reveal cytoskeletal protein variants to disrupt the cardiomyocyte structure and trigger DNA damage, exploration of the pathophysiological mechanisms of genetic AF is still in its infancy. In this review, we provide an overview of cytoskeletal (-associated) gene variants that relate to genetic AF and highlight potential pathophysiological pathways that drive this arrhythmia.
Topics: Atrial Fibrillation; Cytoskeletal Proteins; Humans; Hypertension; Exome Sequencing
PubMed: 35159226
DOI: 10.3390/cells11030416 -
Current Biology : CB Apr 2014
Topics: Actins; Cytoskeletal Proteins; Evolution, Molecular; Intermediate Filaments; Microtubules; Protein Isoforms
PubMed: 24735849
DOI: 10.1016/j.cub.2014.02.003 -
Cells Sep 2022The restoration of an intact epidermal barrier after wound injury is the culmination of a highly complex and exquisitely regulated physiological process involving... (Review)
Review
The restoration of an intact epidermal barrier after wound injury is the culmination of a highly complex and exquisitely regulated physiological process involving multiple cells and tissues, overlapping dynamic events and protein synthesis and regulation. Central to this process is the cytoskeleton, a system of intracellular proteins that are instrumental in regulating important processes involved in wound repair including chemotaxis, cytokinesis, proliferation, migration, and phagocytosis. One highly conserved family of cytoskeletal proteins that are emerging as major regulators of actin and microtubule nucleation, polymerization, and stabilization are the formins. The formin family includes 15 different proteins categorized into seven subfamilies based on three formin homology domains (FH1, FH2, and FH3). The formins themselves are regulated in different ways including autoinhibition, activation, and localization by a range of proteins, including Rho GTPases. Herein, we describe the roles and effects of the formin family of cytoskeletal proteins on the fundamental process of wound healing and highlight recent advances relating to their important functions, mechanisms, and regulation at the molecular and cellular levels.
Topics: Actins; Cytoskeletal Proteins; Formins; Microfilament Proteins; Protein Structure, Tertiary; Wound Healing; rho GTP-Binding Proteins
PubMed: 36139355
DOI: 10.3390/cells11182779 -
Current Biology : CB Feb 2011
Topics: Amino Acid Motifs; Cell Adhesion; Conserved Sequence; Cytoskeletal Proteins; Integrin beta Chains; Membrane Proteins; Models, Biological; Protein Structure, Tertiary; Signal Transduction
PubMed: 21300280
DOI: 10.1016/j.cub.2010.12.002 -
ELife Jun 2022Profilin-1 (PFN1) is a cytoskeletal protein that regulates the dynamics of actin and microtubule assembly. Thus, PFN1 is essential for the normal division, motility, and...
Profilin-1 (PFN1) is a cytoskeletal protein that regulates the dynamics of actin and microtubule assembly. Thus, PFN1 is essential for the normal division, motility, and morphology of cells. Unfortunately, conventional fusion and direct labeling strategies compromise different facets of PFN1 function. As a consequence, the only methods used to determine known PFN1 functions have been indirect and often deduced in cell-free biochemical assays. We engineered and characterized two genetically encoded versions of tagged PFN1 that behave identical to each other and the tag-free protein. In biochemical assays purified proteins bind to phosphoinositide lipids, catalyze nucleotide exchange on actin monomers, stimulate formin-mediated actin filament assembly, and bound tubulin dimers (k = 1.89 µM) to impact microtubule dynamics. In PFN1-deficient mammalian cells, Halo-PFN1 or mApple-PFN1 (mAp-PEN1) restored morphological and cytoskeletal functions. Titrations of self-labeling Halo-ligands were used to visualize molecules of PFN1. This approach combined with specific function-disrupting point-mutants (Y6D and R88E) revealed PFN1 bound to microtubules in live cells. Cells expressing the ALS-associated G118V disease variant did not associate with actin filaments or microtubules. Thus, these tagged PFN1s are reliable tools for studying the dynamic interactions of PFN1 with actin or microtubules in vitro as well as in important cell processes or disease-states.
Topics: Actin Cytoskeleton; Actins; Animals; Cytoskeletal Proteins; Cytoskeleton; Humans; Mammals; Profilins
PubMed: 35666129
DOI: 10.7554/eLife.76485 -
Pflugers Archiv : European Journal of... Jul 2011Titin, the giant elastic ruler protein of striated muscle sarcomeres, contains a catalytic kinase domain related to a family of intrasterically regulated protein... (Review)
Review
Titin, the giant elastic ruler protein of striated muscle sarcomeres, contains a catalytic kinase domain related to a family of intrasterically regulated protein kinases. The most extensively studied member of this branch of the human kinome is the Ca(2+)-calmodulin (CaM)-regulated myosin light-chain kinases (MLCK). However, not all kinases of the MLCK branch are functional MLCKs, and about half lack a CaM binding site in their C-terminal autoinhibitory tail (AI). A unifying feature is their association with the cytoskeleton, mostly via actin and myosin filaments. Titin kinase, similar to its invertebrate analogue twitchin kinase and likely other "MLCKs", is not Ca(2+)-calmodulin-activated. Recently, local protein unfolding of the C-terminal AI has emerged as a common mechanism in the activation of CaM kinases. Single-molecule data suggested that opening of the TK active site could also be achieved by mechanical unfolding of the AI. Mechanical modulation of catalytic activity might thus allow cytoskeletal signalling proteins to act as mechanosensors, creating feedback mechanisms between cytoskeletal tension and tension generation or cellular remodelling. Similar to other MLCK-like kinases like DRAK2 and DAPK1, TK is linked to protein turnover regulation via the autophagy/lysosomal system, suggesting the MLCK-like kinases have common functions beyond contraction regulation.
Topics: Amino Acid Sequence; Animals; Connectin; Cytoskeletal Proteins; Cytoskeleton; Humans; Mechanotransduction, Cellular; Models, Molecular; Molecular Sequence Data; Muscle Proteins; Myosin-Light-Chain Kinase; Phylogeny; Protein Conformation; Protein Folding; Protein Kinases; Protein Unfolding; Sequence Homology, Amino Acid
PubMed: 21416260
DOI: 10.1007/s00424-011-0946-1 -
Cells Nov 2022LIM and SH3 protein 1 was originally identified as a structural cytoskeletal protein with scaffolding function. However, recent data suggest additional roles in cell... (Review)
Review
LIM and SH3 protein 1 was originally identified as a structural cytoskeletal protein with scaffolding function. However, recent data suggest additional roles in cell signaling and gene expression, especially in tumor cells. These novel functions are primarily regulated by the site-specific phosphorylation of LASP1. This review will focus on specific phosphorylation-dependent interaction between LASP1 and cellular proteins that orchestrate primary tumor progression and metastasis. More specifically, we will describe the role of LASP1 in chemokine receptor, and PI3K/AKT signaling. We outline the nuclear role for LASP1 in terms of epigenetics and transcriptional regulation and modulation of oncogenic mRNA translation. Finally, newly identified roles for the cytoskeletal function of LASP1 next to its known canonical F-actin binding properties are included.
Topics: LIM Domain Proteins; Phosphatidylinositol 3-Kinases; Adaptor Proteins, Signal Transducing; Cytoskeletal Proteins; Gene Expression
PubMed: 36497077
DOI: 10.3390/cells11233817 -
Biomolecules Jul 2021Epithelial Protein Lost In Neoplasm (EPLIN), also known as LIMA1 (LIM Domain And Actin Binding 1), was first discovered as a protein differentially expressed in normal... (Review)
Review
Epithelial Protein Lost In Neoplasm (EPLIN), also known as LIMA1 (LIM Domain And Actin Binding 1), was first discovered as a protein differentially expressed in normal and cancerous cell lines. It is now known to be key to the progression and metastasis of certain solid tumours. Despite a slow pace in understanding the biological role in cells and body systems, as well as its clinical implications in the early years since its discovery, recent years have witnessed a rapid progress in understanding the mechanisms of this protein in cells, diseases and indeed the body. EPLIN has drawn more attention over the past few years with its roles expanding from cell migration and cytoskeletal dynamics, to cell cycle, gene regulation, angiogenesis/lymphangiogenesis and lipid metabolism. This concise review summarises and discusses the recent progress in understanding EPLIN in biological processes and its implications in cancer.
Topics: Cytoskeletal Proteins; Gene Expression Regulation, Neoplastic; Humans; Lymphangiogenesis; MicroRNAs; Neoplasms; Neovascularization, Pathologic; Protein Interaction Maps; Signal Transduction; Tumor Suppressor Protein p53
PubMed: 34356662
DOI: 10.3390/biom11071038