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International Journal of Molecular... May 2023The mammalian formin family comprises fifteen multi-domain proteins that regulate actin dynamics and microtubules in vitro and in cells. Evolutionarily conserved formin... (Review)
Review
The mammalian formin family comprises fifteen multi-domain proteins that regulate actin dynamics and microtubules in vitro and in cells. Evolutionarily conserved formin homology (FH) 1 and 2 domains allow formins to locally modulate the cell cytoskeleton. Formins are involved in several developmental and homeostatic processes, as well as human diseases. However, functional redundancy has long hampered studies of individual formins with genetic loss-of-function approaches and prevents the rapid inhibition of formin activities in cells. The discovery of small molecule inhibitor of formin homology 2 domains (SMIFH2) in 2009 was a disruptive change that provided a powerful chemical tool to explore formins' functions across biological scales. Here, I critically discuss the characterization of SMIFH2 as a pan-formin inhibitor, as well as growing evidence of unexpected off-target effects. By collating the literature and information hidden in public repositories, outstanding controversies and fundamental open questions about the substrates and mechanism of action of SMIFH2 emerge. Whenever possible, I propose explanations for these discrepancies and roadmaps to address the paramount open questions. Furthermore, I suggest that SMIFH2 be reclassified as a multi-target inhibitor for its appealing activities on proteins involved in pathological formin-dependent processes. Notwithstanding all drawbacks and limitations, SMIFH2 will continue to prove useful in studying formins in health and disease in the years to come.
Topics: Animals; Humans; Formins; Microfilament Proteins; Actins; Cytoskeleton; Biology; Actin Cytoskeleton; Mammals
PubMed: 37240404
DOI: 10.3390/ijms24109058 -
Cell Jul 2010
Topics: Actins; Animals; Cell Shape; Disease; Humans; Microfilament Proteins; Signal Transduction; rho GTP-Binding Proteins
PubMed: 20603022
DOI: 10.1016/j.cell.2010.06.030 -
Cancer Science Oct 2017Cancer is a polygenic disease characterized by uncontrolled growth of normal body cells, deregulation of the cell cycle as well as resistance to apoptosis. The... (Review)
Review
Cancer is a polygenic disease characterized by uncontrolled growth of normal body cells, deregulation of the cell cycle as well as resistance to apoptosis. The spectraplakin protein microtubule actin cross-linking factor 1 (MACF1) plays an essential function in various cellular processes, including cell proliferation, migration, signaling transduction and embryo development. MACF1 is also involved in processes such as metastatic invasion in which cytoskeleton organization is a critical element that contributes to tumor progression in various human cancers. Aberrant expression of MACF1 initiates the tumor cell proliferation, and migration and metastasis in numerous cancers, such as breast cancer, colon cancer, lung cancer and glioblastoma. In this review, we summarized the current knowledge of MACF1 and its critical role in different human cancers. This will be helpful for researchers to investigate the novel functional role of MACF1 in human cancers and as a potential target to enhance the efficacy of therapeutic treatment modalities.
Topics: Alternative Splicing; Cell Movement; Cell Proliferation; Disease Progression; Humans; Microfilament Proteins; Neoplasm Invasiveness; Neoplasms; Signal Transduction
PubMed: 28782898
DOI: 10.1111/cas.13344 -
Journal of Biochemistry Sep 2003Rapid reorganization of the actin cytoskeleton underlies morphological changes and motility of cells. WASP family proteins have received a great deal of attention as the... (Review)
Review
Rapid reorganization of the actin cytoskeleton underlies morphological changes and motility of cells. WASP family proteins have received a great deal of attention as the signal-regulated molecular switches that initiate actin polymerization. The first member, WASP, was identified as the product of a gene of which dysfunction causes the human hereditary disease Wiskott-Aldrich syndrome. There are now five members in this protein family, namely WASP, N-WASP, WAVE/Scar1, 2, and 3. WASP and N-WASP have functional and physical associations with Cdc42, a Rho family small GTPase involved in filopodium formation. In contrast, there is evidence that links the WAVE/Scar proteins with another Rho family protein, Rac, which is a regulator of membrane ruffling. All WASP family members have a VCA domain at the C-terminus through which Arp2/3 complex is activated to nucleate actin polymerization. Analyses of model organisms have just begun to reveal unexpected functions of WASP family proteins in multicellular organisms.
Topics: Actins; Animals; Gene Expression Regulation; Humans; Microfilament Proteins; Models, Biological; Proteins; Wiskott-Aldrich Syndrome Protein; Wiskott-Aldrich Syndrome Protein Family; rac GTP-Binding Proteins
PubMed: 14561714
DOI: 10.1093/jb/mvg146 -
Current Opinion in Cell Biology Feb 2006Filopodia are rod-like cell surface projections filled with bundles of parallel actin filaments. They are found on a variety of cell types and have been ascribed sensory... (Review)
Review
Filopodia are rod-like cell surface projections filled with bundles of parallel actin filaments. They are found on a variety of cell types and have been ascribed sensory or exploratory functions. Filopodium formation is frequently associated with protrusion of sheet-like actin filament arrays called lamellipodia and membrane ruffles, but, in comparison to these structures, the molecular details underpinning the initiation and maintenance of filopodia are only just beginning to emerge. Recent advances have improved our understanding of the molecular requirements for filopodium protrusion and have yielded insights into the inter-relationships between lamellipodia and filopodia, the two 'sub-compartments' of the protrusive actin cytoskeleton.
Topics: Animals; Dictyostelium; Mice; Microfilament Proteins; Models, Biological; Pseudopodia; Signal Transduction
PubMed: 16337369
DOI: 10.1016/j.ceb.2005.11.002 -
Pancreas 2019The pathogenesis of pancreatic neuroendocrine tumors (PNETs) is still unclear. We propose Frabin as a new molecular alteration in PNETs. Frabin is a guanine nucleotide...
OBJECTIVE
The pathogenesis of pancreatic neuroendocrine tumors (PNETs) is still unclear. We propose Frabin as a new molecular alteration in PNETs. Frabin is a guanine nucleotide exchange factor playing a role in mediating actin cytoskeleton changes during cell migration, morphogenesis, polarization, and division.
METHODS
Patients with PNETs of different grades were assessed for Frabin expression using immunohistochemistry and tissue microarray. The tissue microarray included 12 grade 1 and 3 grade 2 PNETs and 14 grade 3 pancreatic neuroendocrine carcinomas (PECAs). Frabin immunostain was scored with Allred system. Statistical analysis used SAS and R software. Immunohistochemistry scores were correlated with tumor grade and stage. The Spearman correlation coefficient was calculated with P values.
RESULTS
Pancreatic neuroendocrine tumors were graded according to the World Health Organization 2017 guidelines. Frabin was expressed by 24 (82.7%) of the PNET/PECA studied. Only 5 (17.2%) of the 29 PNETs/PECA evaluated were Frabin negative. Frabin expression was cytoplasmic in all cases. We found a significant positive correlation (ρ = 0.47) between Frabin immunohistochemistry score and tumor grade (P = 0.01). No correlation was found between Frabin expression and tumor stage (P = 0.91).
CONCLUSIONS
We report Frabin overexpression as a novel molecular alteration occurring in PNETs/PECAs.
Topics: Adult; Aged; Female; Humans; Immunohistochemistry; Male; Microfilament Proteins; Middle Aged; Neoplasm Grading; Neuroendocrine Tumors; Pancreatic Neoplasms
PubMed: 31688594
DOI: 10.1097/MPA.0000000000001422 -
The Journal of Cell Biology Jul 1999
Review
Topics: Actin Depolymerizing Factors; Actins; Animals; Cell Adhesion Molecules; Cell Cycle Proteins; Destrin; GTP-Binding Proteins; Gelsolin; Humans; Microfilament Proteins; Models, Biological; Phosphoproteins; Proteins; Signal Transduction; Wiskott-Aldrich Syndrome Protein; cdc42 GTP-Binding Protein
PubMed: 10427083
DOI: 10.1083/jcb.146.2.267 -
Scientific Reports Dec 2016The WD40 proteins, often acting as scaffolds to form functional complexes in fundamental cellular processes, are one of the largest families encoded by the eukaryotic...
The WD40 proteins, often acting as scaffolds to form functional complexes in fundamental cellular processes, are one of the largest families encoded by the eukaryotic genomes. Systematic studies of this family on genome scale are highly required for understanding their detailed functions, but are currently lacking in the animal lineage. Here we present a comprehensive in silico study of the human WD40 family. We have identified 262 non-redundant WD40 proteins, and grouped them into 21 classes according to their domain architectures. Among them, 11 animal-specific domain architectures have been recognized. Sequence alignment indicates the complicated duplication and recombination events in the evolution of this family. Through further phylogenetic analysis, we have revealed that the WD40 family underwent more expansion than the overall average in the evolutionary early stage, and the early emerged WD40 proteins are prone to domain architectures with fundamental cellular roles and more interactions. While most widely and highly expressed human WD40 genes originated early, the tissue-specific ones often have late origin. These results provide a landscape of the human WD40 family concerning their classification, evolution, and expression, serving as a valuable complement to the previous studies in the plant lineage.
Topics: Amino Acid Sequence; Animals; Cluster Analysis; Evolution, Molecular; Genome, Human; Humans; Microfilament Proteins; Multigene Family; Phylogeny; Plant Proteins; Plants; Sequence Alignment
PubMed: 27991561
DOI: 10.1038/srep39262 -
Biochemical and Biophysical Research... Nov 2018Actin-depolymerizing factor (ADF)/cofilin and actin-interacting protein 1 (AIP1), also known as WD-repeat protein 1 (WDR1), are conserved among eukaryotes and play... (Review)
Review
Actin-depolymerizing factor (ADF)/cofilin and actin-interacting protein 1 (AIP1), also known as WD-repeat protein 1 (WDR1), are conserved among eukaryotes and play critical roles in dynamic reorganization of the actin cytoskeleton. AIP1 preferentially promotes disassembly of ADF/cofilin-decorated actin filaments but exhibits minimal effects on bare actin filaments. Therefore, AIP1 has been often considered to be an ancillary co-factor of ADF/cofilin that merely boosts ADF/cofilin activity level. However, genetic and cell biological studies show that AIP1 deficiency often causes lethality or severe abnormalities in multiple tissues and organs including muscle, epithelia, and blood, suggesting that AIP1 is a major regulator of many biological processes that depend on actin dynamics. This review summarizes recent progress in studies on the biochemical mechanism of actin filament severing by AIP1 and in vivo functions of AIP1 in model organisms and human diseases.
Topics: Actin Cytoskeleton; Actin Depolymerizing Factors; Actins; Animals; Destrin; Eukaryotic Cells; Fungi; Gene Expression Regulation; Humans; Immunologic Deficiency Syndromes; Kinetics; Microfilament Proteins; Molecular Dynamics Simulation; Mutation; Plants; Signal Transduction
PubMed: 29056508
DOI: 10.1016/j.bbrc.2017.10.096 -
Cell Motility and the Cytoskeleton 1990
Review
Topics: Actins; Animals; Contractile Proteins; Humans; Microfilament Proteins; Mutation; Profilins
PubMed: 2257632
DOI: 10.1002/cm.970170202