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Research Interests: Genetics, Physiology, Biology, Cell Migration, Cell Biology, and 15 moreMedicine, Molecular Mechanics, Motility, Molecular and cellular biology, Humans, Animals, Actin Binding Proteins, Actin, Actin Cytoskeleton, Actin Dynamics, Clinical Sciences, Actin Filaments, Lamellipodia, Biochemistry and cell biology, and Cell Motility
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Research Interests: Electron Microscopy, Fluorescence Microscopy, Biology, Transmission Electron Microscopy, Medicine, and 13 moreBiological Sciences, Mice, Animals, Cell Polarity, Actin, Dendrites, Actin Cytoskeleton, Transfection, Pseudopodia, Actin Filaments, Gene Expression Regulation, Microfilaments, and Medical and Health Sciences
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Research Interests: Chemistry, Medical Microbiology, Cell Adhesion, Cell Biology, Medicine, and 14 moreCytoskeleton, Biological Sciences, Motility, Keratinocytes, Animals, Physical sciences, Microtubule Dynamics, Actin, Microtubules, Actin Cytoskeleton, Human Fibroblasts, Biochemistry and cell biology, Rho, and fibroblasts
Page 1. © 1999 Macmillan Magazines Ltd brief communications NATURE CELL BIOLOGY | VOL 1 | SEPTEMBER 1999 | cellbio.nature.com 321 VASP dynamics during lamellipodia protrusion Klemens Rottner*, Barbara Behrendt ...
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A microtubule-tracking protein amplifies actin assembly Cells of all kingdoms form a rigid but dynamic cytoskeleton that is essential for cell shape and growth. Microtubules and actin filaments build the eukaryotic cytoskeleton, and... more
A microtubule-tracking protein amplifies actin assembly Cells of all kingdoms form a rigid but dynamic cytoskeleton that is essential for cell shape and growth. Microtubules and actin filaments build the eukaryotic cytoskeleton, and although they serve distinct functions, cooperation and indirect connections between these systems exist (1). On page 1004 of this issue, Henty-Ridilla et al. (2) report how a protein that accumulates at the growing tips of microtubules also elongates actin filaments, revealing an unexpected interaction between the two cytoskeletal systems.
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Pathogenic bacteria possess a great potential of causing infectious diseases and represent a serious threat to human and animal health. Understanding the molecular basis of infection development can provide new valuable strategies for... more
Pathogenic bacteria possess a great potential of causing infectious diseases and represent a serious threat to human and animal health. Understanding the molecular basis of infection development can provide new valuable strategies for disease prevention and better control. In host‐pathogen interactions, actin‐cytoskeletal dynamics play a crucial role in the successful adherence, invasion, and intracellular motility of many intruding microbial pathogens. Cortactin, a major cellular factor that promotes actin polymerization and other functions, appears as a central regulator of host‐pathogen interactions and different human diseases including cancer development. Various important microbes have been reported to hijack cortactin signaling during infection. The primary regulation of cortactin appears to proceed via serine and/or tyrosine phosphorylation events by upstream kinases, acetylation, and interaction with various other host proteins, including the Arp2/3 complex, filamentous actin, the actin nucleation promoting factor N‐WASP, focal adhesion kinase FAK, the large GTPase dynamin‐2, the guanine nucleotide exchange factor Vav2, and the actin‐stabilizing protein CD2AP. Given that many signaling factors can affect cortactin activities, several microbes target certain unique pathways, while also sharing some common features. Here we review our current knowledge of the hallmarks of cortactin as a major target for eminent Gram‐negative and Gram‐positive bacterial pathogens in humans.
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Mutasynthesis of pyrichalasin H from Magnaporthe grisea NI980 yielded a series of unprecedented 4′‐substituted cytochalasin analogues in titres as high as the wild‐type system (≈60 mg L−1). Halogenated, O‐alkyl, O‐allyl and O‐propargyl... more
Mutasynthesis of pyrichalasin H from Magnaporthe grisea NI980 yielded a series of unprecedented 4′‐substituted cytochalasin analogues in titres as high as the wild‐type system (≈60 mg L−1). Halogenated, O‐alkyl, O‐allyl and O‐propargyl examples were formed, as well as a 4′‐azido analogue. 4′‐O‐Propargyl and 4′‐azido analogues reacted smoothly in Huisgen cycloaddition reactions, whereas p‐Br and p‐I compounds reacted in Pd‐catalysed cross‐coupling reactions. A series of examples of biotin‐linked, dye‐linked and dimeric cytochalasins was rapidly created. In vitro and in vivo bioassays of these compounds showed that the 4′‐halogenated and azido derivatives retained their cytotoxicity and antifungal activities; but a unique 4′‐amino analogue was inactive. Attachment of larger substituents attenuated the bioactivities. In vivo actin‐binding studies with adherent mammalian cells showed that actin remains the likely intracellular target. Dye‐linked compounds revealed visualisation of intracellular actin structures even in the absence of phalloidin, thus constituting a potential new class of actin‐visualisation tools with filament‐barbed end‐binding specificity.
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The actin cytoskeleton is essential for morphogenesis and virtually all types of cell shape changes. Reorganization is per definition driven by continuous disassembly and re-assembly of actin filaments, controlled by major, ubiquitously... more
The actin cytoskeleton is essential for morphogenesis and virtually all types of cell shape changes. Reorganization is per definition driven by continuous disassembly and re-assembly of actin filaments, controlled by major, ubiquitously operating machines. These are specifically employed by the cell to tune its activities in accordance with respective environmental conditions or to satisfy specific needs.Here we sketch some fundamental signalling pathways established to contribute to the reorganization of specific actin structures at the plasma membrane. Rho-family GTPases are at the core of these pathways, and dissection of their precise contributions to actin reorganization in different cell types and tissues will thus continue to improve our understanding of these important signalling nodes. Furthermore, we will draw your attention to the emerging theme of actin reorganization on intracellular membranes, its functional relation to Rho-GTPase signalling, and its relevance for the exciting phenomenon autophagy.
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Research Interests: Chemistry, Stem Cells, Cell Biology, Cell Signaling, Biological Chemistry, and 15 moreMedicine, Cytoskeleton, Biological Sciences, Cell Differentiation, Mesenchymal Stem Cell, Molecular Cell Biology, CHEMICAL SCIENCES, CDC, Rac, Sma, P, Rho GTPase, RhoA, Myofibroblast, and Medical and Health Sciences
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Enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC), two closely related diarrhoeagenic pathogens, induce actin rearrangements at the surface of infected host cells resulting in the formation of pseudopod-like... more
Enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC), two closely related diarrhoeagenic pathogens, induce actin rearrangements at the surface of infected host cells resulting in the formation of pseudopod-like structures termed pedestals beneath intimately attached bacteria. We have shown previously that N-WASP, a key integrator of signalling pathways that regulate actin polymerization via the Arp2/3 complex, is essential for pedestal formation induced by EPEC using N-WASP-defective cell lines. Here we show that actin pedestal formation initiated by EHEC also depends on N-WASP. Amino acid residues 226-274 of N-WASP are both necessary and sufficient to target N-WASP to sites of EHEC attachment. The recruitment mechanism thus differs from that used by EPEC, in which amino-terminal sequences of N-WASP mediate recruitment. For EPEC, recruitment of N-WASP downstream of Nck has been postulated to be mediated by WIP. However, we find a direct interaction of N-WASP with WIP to be dispensable for EPEC-induced pedestal formation and present data supporting an F-actin-dependent localization of WIP to actin pedestals induced by both EPEC and EHEC. In summary, our data show that EPEC and EHEC use different mechanisms to recruit N-WASP, which is essential for actin pedestal formation induced by both pathogens.
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Research Interests: Biology, Cell Biology, Biological Chemistry, Medicine, Biological Sciences, and 15 moreBrain, Humans, Movement, Mice, Animals, Biological, Proteins, CHEMICAL SCIENCES, Vesicle, Base Sequence, Phosphatidylinositol, Molecular Sequence Data, fibroblasts, reverse transcriptase polymerase chain reaction, and Medical and Health Sciences
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Hematopoietic-specific protein 1 (Hem1) is an essential subunit of the WAVE regulatory complex (WRC) in immune cells. WRC is crucial for Arp2/3 complex activation and the protrusion of branched actin filament networks. Moreover, Hem1 loss... more
Hematopoietic-specific protein 1 (Hem1) is an essential subunit of the WAVE regulatory complex (WRC) in immune cells. WRC is crucial for Arp2/3 complex activation and the protrusion of branched actin filament networks. Moreover, Hem1 loss of function in immune cells causes autoimmune diseases in humans. Here, we show that genetic removal of Hem1 in macrophages diminishes frequency and efficacy of phagocytosis as well as phagocytic cup formation in addition to defects in lamellipodial protrusion and migration. Moreover, Hem1-null macrophages displayed strong defects in cell adhesion despite unaltered podosome formation and concomitant extracellular matrix degradation. Specifically, dynamics of both adhesion and de-adhesion as well as concomitant phosphorylation of paxillin and focal adhesion kinase (FAK) were significantly compromised. Accordingly, disruption of WRC function in non-hematopoietic cells coincided with both defects in adhesion turnover and altered FAK and paxillin phosphorylation. Consistently, platelets exhibited reduced adhesion and diminished integrin αIIbβ3 activation upon WRC removal. Interestingly, adhesion phenotypes, but not lamellipodia formation, were partially rescued by small molecule activation of FAK. A full rescue of the phenotype, including lamellipodia formation, required not only the presence of WRCs but also their binding to and activation by Rac. Collectively, our results uncover that WRC impacts on integrin-dependent processes in a FAK-dependent manner, controlling formation and dismantling of adhesions, relevant for properly grabbing onto extracellular surfaces and particles during cell edge expansion, like in migration or phagocytosis.
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Research Interests: Fluorescence Microscopy, Biology, Cell Biology, Medicine, Cytoskeleton, and 15 moreBiological Sciences, Cell line, Escherichia coli, Mice, Animals, Actin, Actin Dynamics, Filopodia, CHEMICAL SCIENCES, Gene Targeting, Human Fibroblasts, Biochemistry and cell biology, fibroblasts, alleles, and Medical and Health Sciences
Changes in vascular permeability are a hallmark of inflammatory processes. The actin cytoskeleton plays a crucial role in regulating endothelial cell contacts and thus permeability. We showed that the actin‐binding protein cortactin... more
Changes in vascular permeability are a hallmark of inflammatory processes. The actin cytoskeleton plays a crucial role in regulating endothelial cell contacts and thus permeability. We showed that the actin‐binding protein cortactin (CTTN) regulates vascular permeability in vivo via Rap1. However, it is not known if the actin cytoskeleton contributes to increased permeability after loss of CTTN. In a mass spectrometric analysis, we found Rho‐kinase1 (ROCK1) to be induced 2.7‐fold in cortactin‐KO endothelium. This was confirmed by Western blot and immunolabelling of tissues from CTTN‐KO mice. Concomitantly, we observed increased phosphorylation of MLC and more stress fibers in CTTN‐KO endothelium. Secretion of the hormone adrenomedullin (ADM), which activates Rap1 and counteracts formation of stress fibers, is reduced in CTTN‐KO serum and supernatant of CTTN‐depleted endothelium. Importantly, inhibition of ROCK1 or ADM administration rescued the effect on permeability provoked by loss of CTTN. Our data suggest that CTTN controls the molecular machinery necessary for the regulation of actomyosin contractility and vascular permeability.Grant Funding Source: Supported by CONACYT 179895
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... dent. Blebs on the other hand result from membrane bulging through locally induced flexibility of the cell cortex, coupled with cytoplasmic flow driven by actomyosin-dependent intracellular pressure (Charras and Paluch, 2008). ...
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Research Interests: Biology, Cell Biology, Biological Chemistry, Medicine, Cytoskeleton, and 15 moreBiological Sciences, Humans, Magnesium, Biological, Metals, CHEMICAL SCIENCES, Molecular cloning, Guanosine Triphosphate, CDC, Protein Conformation, Protein Binding, Ions, Nucleotides, GTP, and Medical and Health Sciences
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Actin filaments generate mechanical forces that drive membrane movements during trafficking, endocytosis and cell migration. Reciprocally, adaptations of actin networks to forces regulate their assembly and architecture. Yet, a... more
Actin filaments generate mechanical forces that drive membrane movements during trafficking, endocytosis and cell migration. Reciprocally, adaptations of actin networks to forces regulate their assembly and architecture. Yet, a demonstration of forces acting on actin regulators at actin assembly sites in cells is missing. Here we show that local forces arising from actin filament elongation mechanically control WAVE regulatory complex (WRC) dynamics and function, that is, Arp2/3 complex activation in the lamellipodium. Single-protein tracking revealed WRC lateral movements along the lamellipodium tip, driven by elongation of actin filaments and correlating with WRC turnover. The use of optical tweezers to mechanically manipulate functional WRC showed that piconewton forces, as generated by single-filament elongation, dissociated WRC from the lamellipodium tip. WRC activation correlated with its trapping, dwell time and the binding strength at the lamellipodium tip. WRC crosslinking, hindering its mechanical dissociation, increased WRC dwell time and Arp2/3-dependent membrane protrusion. Thus, forces generated by individual actin filaments on their regulators can mechanically tune their turnover and hence activity during cell migration.