scholarly journals The Actin-Family Protein Arp4 Is a Novel Suppressor for the Formation and Functions of Nuclear F-Actin

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 758 ◽  
Author(s):  
Shota Yamazaki ◽  
Christian Gerhold ◽  
Koji Yamamoto ◽  
Yuya Ueno ◽  
Robert Grosse ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Critical Role ◽  
Strand Break ◽  
Xenopus Laevis Oocytes ◽  
Actin Assembly ◽  
Nih3t3 Cells ◽  
Damage Repair ◽  
Family Protein ◽  
Related Proteins ◽  
Inducible Gene

The crosstalk between actin and actin-related proteins (Arps), namely Arp2 and Arp3, plays a central role in facilitating actin polymerization in the cytoplasm and also in the nucleus. Nuclear F-actin is required for transcriptional regulation, double-strand break repair, and nuclear organization. The formation of nuclear F-actin is highly dynamic, suggesting the involvement of positive and negative regulators for nuclear actin polymerization. While actin assembly factors for nuclear F-actin have been recently described, information about inhibitory factors is still limited. The actin-related protein Arp4 which is predominantly localized in the nucleus, has been previously identified as an integral subunit of multiple chromatin modulation complexes, where it forms a heterodimer with monomeric actin. Therefore, we tested whether Arp4 functions as a suppressor of nuclear F-actin formation. The knockdown of Arp4 (Arp4 KD) led to an increase in nuclear F-actin formation in NIH3T3 cells, and purified Arp4 potently inhibited F-actin formation in mouse nuclei transplanted into Xenopus laevis oocytes. Consistently, Arp4 KD facilitated F-actin-inducible gene expression (e.g., OCT4) and DNA damage repair. Our results suggest that Arp4 has a critical role in the formation and functions of nuclear F-actin.

scholarly journals The Human Arp2/3 Complex Is Composed of Evolutionarily Conserved Subunits and Is Localized to Cellular Regions of Dynamic Actin Filament Assembly

1997 ◽  
Vol 138 (2) ◽  
pp. 375-384 ◽  
Author(s):  
Matthew D. Welch ◽  
Angela H. DePace ◽  
Suzie Verma ◽  
Akihiro Iwamatsu ◽  
Timothy J. Mitchison
Keyword(s):  
Actin Polymerization ◽  
Predicted Amino Acid Sequence ◽  
Actin Assembly ◽  
Filament Assembly ◽  
Evolutionarily Conserved ◽  
And Function ◽  
Related Proteins ◽  
Human Complex ◽  
Novel Protein ◽  
In Cells

The Arp2/3 protein complex has been implicated in the control of actin polymerization in cells. The human complex consists of seven subunits which include the actin related proteins Arp2 and Arp3, and five others referred to as p41-Arc, p34-Arc, p21-Arc, p20-Arc, and p16-Arc (Arp complex). We have determined the predicted amino acid sequence of all seven subunits. Each has homologues in diverse eukaryotes, implying that the structure and function of the complex has been conserved through evolution. Human Arp2 and Arp3 are very similar to family members from other species. p41-Arc is a new member of the Sop2 family of WD (tryptophan and aspartate) repeat–containing proteins and may be posttranslationally modified, suggesting that it may be involved in regulating the activity and/or localization of the complex. p34-Arc, p21-Arc, p20-Arc, and p16-Arc define novel protein families. We sought to evaluate the function of the Arp2/3 complex in cells by determining its intracellular distribution. Arp3, p34-Arc, and p21-Arc were localized to the lamellipodia of stationary and locomoting fibroblasts, as well to Listeria monocytogenes assembled actin tails. They were not detected in cellular bundles of actin filaments. Taken together with the ability of the Arp2/3 complex to induce actin polymerization, these observations suggest that the complex promotes actin assembly in lamellipodia and may participate in lamellipodial protrusion.

scholarly journals Scd5p Mediates Phosphoregulation of Actin and Endocytosis by the Type 1 Phosphatase Glc7p in Yeast

2007 ◽  
Vol 18 (12) ◽  
pp. 4885-4898 ◽  
Author(s):  
Guisheng Zeng ◽  
Bo Huang ◽  
Suat Peng Neo ◽  
Junxia Wang ◽  
Mingjie Cai
Keyword(s):  
Cell Growth ◽  
Actin Polymerization ◽  
Binding Protein ◽  
Actin Assembly ◽  
Endocytic Vesicle ◽  
Actin Organization ◽  
Related Proteins ◽  
Type 1 Phosphatase ◽  
Endocytic Proteins

Pan1p plays essential roles in both actin and endocytosis in yeast. It interacts with, and regulates the function of, multiple endocytic proteins and actin assembly machinery. Phosphorylation of Pan1p by the kinase Prk1p down-regulates its activity, resulting in disassembly of the endocytic vesicle coat complex and termination of vesicle-associated actin polymerization. In this study, we focus on the mechanism that acts to release Pan1p from phosphorylation inhibition. We show that Pan1p is dephosphorylated by the phosphatase Glc7p, and the dephosphorylation is dependent on the Glc7p-targeting protein Scd5p, which itself is a phosphorylation target of Prk1p. Scd5p links Glc7p to Pan1p in two ways: directly by interacting with Pan1p and indirectly by interacting with the Pan1p-binding protein End3p. Depletion of Glc7p from the cells causes defects in cell growth, actin organization, and endocytosis, all of which can be partially suppressed by deletion of the PRK1 gene. These results suggest that Glc7p antagonizes the activity of the Prk1p kinase in regulating the functions of Pan1p and possibly other actin- and endocytosis-related proteins.

scholarly journals Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 821
Author(s):  
Wanglong Qiu ◽  
Chia-Yu Kuo ◽  
Yu Tian ◽  
Gloria H. Su
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Critical Role ◽  
Genetic Mutations ◽  
Cancer Genetic ◽  
Dual Roles ◽  
Activin Signaling ◽  
Physiological Processes ◽  
Cancer Types ◽  
Related Proteins

Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, indicating that activin signaling plays a critical role in tumorigenesis. Recent evidence reveals that activin signaling may function as a tumor-suppressor in tumor initiation, and a promoter in the later progression and metastasis of tumors. This article reviews many aspects of activin, including the signaling cascade of activin, activin-related proteins, and its role in tumorigenesis, particularly in pancreatic cancer development. The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases.

scholarly journals Coordinated regulation of platelet actin filament barbed ends by gelsolin and capping protein.

1996 ◽  
Vol 134 (2) ◽  
pp. 389-399 ◽  
Author(s):  
K Barkalow ◽  
W Witke ◽  
D J Kwiatkowski ◽  
J H Hartwig
Keyword(s):  
Actin Cytoskeleton ◽  
Actin Filament ◽  
Actin Polymerization ◽  
Residual Activity ◽  
Human Platelets ◽  
Actin Assembly ◽  
Capping Protein ◽  
Capping Proteins ◽  
End Capping ◽  
Human And Mouse

Exposure of cryptic actin filament fast growing ends (barbed ends) initiates actin polymerization in stimulated human and mouse platelets. Gelsolin amplifies platelet actin assembly by severing F-actin and increasing the number of barbed ends. Actin filaments in stimulated platelets from transgenic gelsolin-null mice elongate their actin without severing. F-actin barbed end capping activity persists in human platelet extracts, depleted of gelsolin, and the heterodimeric capping protein (CP) accounts for this residual activity. 35% of the approximately 5 microM CP is associated with the insoluble actin cytoskeleton of the resting platelet. Since resting platelets have an F-actin barbed end concentration of approximately 0.5 microM, sufficient CP is bound to cap these ends. CP is released from OG-permeabilized platelets by treatment with phosphatidylinositol 4,5-bisphosphate or through activation of the thrombin receptor. However, the fraction of CP bound to the actin cytoskeleton of thrombin-stimulated mouse and human platelets increases rapidly to approximately 60% within 30 s. In resting platelets from transgenic mice lacking gelsolin, which have 33% more F-actin than gelsolin-positive cells, there is a corresponding increase in the amount of CP associated with the resting cytoskeleton but no change with stimulation. These findings demonstrate an interaction between the two major F-actin barbed end capping proteins of the platelet: gelsolin-dependent severing produces barbed ends that are capped by CP. Phosphatidylinositol 4,5-bisphosphate release of gelsolin and CP from platelet cytoskeleton provides a mechanism for mediating barbed end exposure. After actin assembly, CP reassociates with the new actin cytoskeleton.

scholarly journals The emerging role of RNAs in DNA damage repair

2017 ◽  
Vol 24 (4) ◽  
pp. 580-587 ◽  
Author(s):  
Ben R Hawley ◽  
Wei-Ting Lu ◽  
Ania Wilczynska ◽  
Martin Bushell
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Critical Role ◽  
Repair Process ◽  
Rna Molecules ◽  
Processing Enzymes ◽  
Damage Repair ◽  
New Findings ◽  
Integral Role ◽  
Repair Mechanisms

Abstract Many surveillance and repair mechanisms exist to maintain the integrity of our genome. All of the pathways described to date are controlled exclusively by proteins, which through their enzymatic activities identify breaks, propagate the damage signal, recruit further protein factors and ultimately resolve the break with little to no loss of genetic information. RNA is known to have an integral role in many cellular pathways, but, until very recently, was not considered to take part in the DNA repair process. Several reports demonstrated a conserved critical role for RNA-processing enzymes and RNA molecules in DNA repair, but the biogenesis of these damage-related RNAs and their mechanisms of action remain unknown. We will explore how these new findings challenge the idea of proteins being the sole participants in the response to DNA damage and reveal a new and exciting aspect of both DNA repair and RNA biology.

scholarly journals Identification of AKT-regulated genes in inducible MERAkt cells

2001 ◽  
Vol 7 (2) ◽  
pp. 105-114 ◽  
Author(s):  
IRENE KUHN ◽  
MARTY F. BARTHOLDI ◽  
HUGH SALAMON ◽  
RICHARD I. FELDMAN ◽  
RICHARD A. ROTH ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Cdna Array ◽  
Signal Transduction Pathway ◽  
Transforming Growth Factor Β ◽  
Oncogenic Transformation ◽  
Nih3t3 Cells ◽  
Estrogen Receptor Ligands ◽  
Phosphoinositide 3 Kinase

AKT/protein kinase B plays a critical role in the phosphoinositide 3-kinase (PI3-kinase) pathway regulating cell growth, differentiation, and oncogenic transformation. Akt1-regulated genes were identified by cDNA array hybridization analysis using an inducible AKT1 protein, MERAKT. Treatment of MERAkt cells with estrogen receptor ligands resulted in phosphorylative activation of MERAKT. Genes differentially expressed in MERAkt/NIH3T3 cells treated with tamoxifen, raloxifene, ICI-182780, and ZK955, were identified at 3 and 20 h. AKT activation resulted in the repression of c-myc, early growth response 1 (EGR1), transforming growth factor β receptor III (TGF-βr III), and thrombospondin-1 (THBS1). Although c-myc induction is often associated with oncogenic transformation, the c-myc repression observed here is consistent with the anti-apoptotic function of AKT. Repression of THBS1 and EGR1 is consistent with the known pro-angiogenic functions of AKT. AKT-regulated genes were found to be largely distinct from platelet-derived growth factor-β (PDGFβ)-regulated genes; only T-cell death-associated gene 51 (TDAG51) was induced in both cases. In contrast to their repression by AKT, c-myc, THBS1, and EGR1 were induced by PDGFβ, indicating negative interference between elements upstream and downstream of AKT1 in the PDGFβ signal transduction pathway.

scholarly journals Quantifying Epithelial Plasticity as a Platform to Reverse Epithelial Injury

2020 ◽  
Author(s):  
Kristine Nishida ◽  
Baishakhi Ghosh ◽  
Lakshmana Chandrala ◽  
Saborny Mahmud ◽  
Si Chen ◽  
...  
Keyword(s):  
Correlation Length ◽  
Actin Polymerization ◽  
Critical Role ◽  
Cell Movement ◽  
Cellular Damage ◽  
Chronic Obstructive ◽  
Phenotypic Analysis ◽  
Velocity Correlation ◽  
Epithelial Plasticity ◽  
Large Patient

AbstractEpithelial surfaces lining the lung serve as the primary environmental gaseous interface, and are subject to common life-limiting diseases, including COPD (Chronic Obstructive Pulmonary Disease). Despite the critical role of epithelial cells in pulmonary health and disease, quantitative models are lacking but are required given the large patient to patient variability to characterize the epithelial plasticity that follows injury. We have identified a series of assessments to quantitatively identify the changes that occur in the epithelium and to identify targets that reverse injury. The injured epithelium has decreased ciliary function and monolayer height, which in the case of cells derived from COPD patients results in an overall disorganization of structure. Injury causes the cells to shift to an unjammed state, with corresponding increases in the velocity correlation length implicating cell shape and stiffness as fundamental to the injury response. Specific inhibitors of actin polymerization (LatA), of MAPK/ERK kinase (U0126) and Nrf-2 pathway activation (CDDO-Me) push the epithelium back towards a jammed state with decreased cell movement and correlation length, as well as improve barrier function and CBF. These studies attest to cell intrinsic properties that allow for a transition to an unjammed state, and that quantitative phenotypic analysis can identify potential specific pharmacologic targets in a given patient and provide insight into basic mechanisms of cellular damage.One Sentence SummaryEnvironmental toxins undermine tissue integrity by manipulating transitions from jammed to unjammed states, thereby mimicking or inducing disease.

scholarly journals A new form of actin assembly around the Shigella-containing vacuole regulates its intracellular niche

2020 ◽  
Author(s):  
Sonja Kühn ◽  
John Bergqvist ◽  
Laura Barrio ◽  
Stephanie Lebreton ◽  
Chiara Zurzolo ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Actin Polymerization ◽  
De Novo ◽  
Shigella Flexneri ◽  
Host Cells ◽  
Host Recognition ◽  
Actin Assembly ◽  
Actin Structure ◽  
New Form ◽  
Structure And Functions

SUMMARYThe enteroinvasive bacterium Shigella flexneri forces its uptake into non-phagocytic host cells through the translocation of T3SS effectors that subvert the actin cytoskeleton. Here, we report de novo actin polymerization after cellular entry around the bacterial containing vacuole (BCV) leading to the formation of a dynamic actin cocoon. This cocoon is thicker than any described cellular actin structure and functions as a gatekeeper for the cytosolic access of the pathogen. Host Cdc42, Toca-1, N-WASP, WIP, the Arp2/3 complex, cortactin, coronin, and cofilin are recruited to the actin cocoon. They are subverted by T3SS effectors, such as IpgD, IpgB1, and IcsB. IcsB immobilizes components of the actin polymerization machinery at the BCV. This represents a novel microbial subversion strategy through localized entrapment of host actin regulators causing massive actin assembly. We propose that the cocoon protects Shigella’s niche from canonical maturation or host recognition.

scholarly journals Coxiella burnetii Induces Reorganization of the Actin Cytoskeleton in Human Monocytes

1998 ◽  
Vol 66 (11) ◽  
pp. 5527-5533 ◽  
Author(s):  
Sonia Meconi ◽  
Véronique Jacomo ◽  
Patrice Boquet ◽  
Didier Raoult ◽  
Jean-Louis Mege ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Coxiella Burnetii ◽  
Actin Polymerization ◽  
Q Fever ◽  
Morphological Changes ◽  
Critical Role ◽  
Filamentous Actin ◽  
Cytoskeleton Reorganization ◽  
Membrane Protrusions ◽  
Actin Protrusions

ABSTRACT Coxiella burnetii, an obligate intracellular bacterium which survives in myeloid cells, causes Q fever in humans. We previously demonstrated that virulent C. burnetiiorganisms are poorly internalized by monocytes compared to avirulent variants. We hypothesized that a differential mobilization of the actin cytoskeleton may account for this distinct phagocytic behavior. Scanning electron microscopy demonstrated that virulent C. burnetii stimulated profound and polymorphic changes in the morphology of THP-1 monocytes, consisting of membrane protrusions and polarized projections. These changes were transient, requiring 5 min to reach their maximum extent and vanishing after 60 min of incubation. In contrast, avirulent variants of C. burnetii did not induce any significant changes in cell morphology. The distribution of filamentous actin (F-actin) was then studied with a specific probe, bodipy phallacidin. Virulent C. burnetii induced a profound and transient reorganization of F-actin, accompanied by an increase in the F-actin content of THP-1 cells. F-actin was colocalized with myosin in cell protrusions, suggesting that actin polymerization and the tension of actin-myosin filaments play a role in C. burnetii-induced morphological changes. In addition, contact between the cell and the bacterium seems to be necessary to induce cytoskeleton reorganization. Bacterial supernatants did not stimulate actin remodeling, and virulent C. burnetii organisms were found in close apposition with F-actin protrusions. The manipulation of the actin cytoskeleton by C. burnetiimay therefore play a critical role in the internalization strategy of this bacterium.

scholarly journals Myosin 1E coordinates actin assembly and cargo trafficking during clathrin-mediated endocytosis

2012 ◽  
Vol 23 (15) ◽  
pp. 2891-2904 ◽  
Author(s):  
Jackie Cheng ◽  
Alexandre Grassart ◽  
David G. Drubin
Keyword(s):  
Mammalian Cells ◽  
Actin Polymerization ◽  
Type I ◽  
Actin Assembly ◽  
Significant Delay ◽  
Src Homology 3 ◽  
Integral Role ◽  
Src Homology 3 Domain ◽  
Src Homology ◽  
Endocytic Vesicles

Myosin 1E (Myo1E) is recruited to sites of clathrin-mediated endocytosis coincident with a burst of actin assembly. The recruitment dynamics and lifetime of Myo1E are similar to those of tagged actin polymerization regulatory proteins. Like inhibition of actin assembly, depletion of Myo1E causes reduced transferrin endocytosis and a significant delay in transferrin trafficking to perinuclear compartments, demonstrating an integral role for Myo1E in these actin-mediated steps. Mistargeting of GFP-Myo1E or its src-homology 3 domain to mitochondria results in appearance of WIP, WIRE, N-WASP, and actin filaments at the mitochondria, providing evidence for Myo1E's role in actin assembly regulation. These results suggest for mammalian cells, similar to budding yeast, interdependence in the recruitment of type I myosins, WIP/WIRE, and N-WASP to endocytic sites for Arp2/3 complex activation to assemble F-actin as endocytic vesicles are being formed.

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