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1.
J Cell Sci ; 133(15)2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32801132

RESUMO

The COVID-19 pandemic has disrupted traditional modes of scientific communication. In-person conferences and seminars have been cancelled and most scientists around the world have been confined to their homes. Although challenging, this situation has presented an opportunity to adopt new ways to communicate science and build scientific relationships within a digital environment, thereby reducing the environmental impact and increasing the inclusivity of scientific events. As a group of researchers who have recently created online seminar series for our respective research communities, we have come together to share our experiences and insights. Only a few weeks into this process, and often learning 'on the job', we have collectively encountered different problems and solutions. Here, we share our advice on formats and tools, security concerns, spreading the word to your community and creating a diverse, inclusive and collegial space online. We hope our experience will help others launch their own online initiatives, helping to shape the future of scientific communication as we move past the current crisis.


Assuntos
Congressos como Assunto , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Ciência , Realidade Virtual , COVID-19 , Segurança Computacional , Humanos , Redes Sociais Online , Pesquisa
2.
Br J Cancer ; 122(4): 517-527, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31844184

RESUMO

BACKGROUND: Docetaxel chemotherapy in prostate cancer has a modest impact on survival. To date, efforts to develop combination therapies have not translated into new treatments. We sought to develop a novel therapeutic strategy to tackle chemoresistant prostate cancer by enhancing the efficacy of docetaxel. METHODS: We performed a drug-repurposing screen by using murine-derived prostate cancer cell lines driven by clinically relevant genotypes. Cells were treated with docetaxel alone, or in combination with drugs (n = 857) from repurposing libraries, with cytotoxicity quantified using High Content Imaging Analysis. RESULTS: Mebendazole (an anthelmintic drug that inhibits microtubule assembly) was selected as the lead drug and shown to potently synergise docetaxel-mediated cell killing in vitro and in vivo. Dual targeting of the microtubule structure was associated with increased G2/M mitotic block and enhanced cell death. Strikingly, following combined docetaxel and mebendazole treatment, no cells divided correctly, forming multipolar spindles that resulted in aneuploid daughter cells. Liposomes entrapping docetaxel and mebendazole suppressed in vivo prostate tumour growth and extended progression-free survival. CONCLUSIONS: Docetaxel and mebendazole target distinct aspects of the microtubule dynamics, leading to increased apoptosis and reduced tumour growth. Our data support a new concept of combined mebendazole/docetaxel treatment that warrants further clinical evaluation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Docetaxel/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Mebendazol/farmacologia , Neoplasias da Próstata , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Sinergismo Farmacológico , Humanos , Masculino , Camundongos , Células PC-3 , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Cell Sci ; 136(5)2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36917211
4.
J Cell Sci ; 132(4)2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30262468

RESUMO

EB proteins track the ends of growing microtubules and regulate microtubule dynamics both directly and by acting as the hub of the tip-tracking network. Mammalian cells express cell type-specific combinations of three EB proteins with different cellular roles. Here, we reconstitute EB1, EB2 and EB3 tip tracking in vitro We find that all three EBs show rapid exchange at the microtubule tip and that their signal correlates to the microtubule assembly rate. However, the three signals differ in their maxima and position from the microtubule tip. Using microtubules built with nucleotide analogues and site-directed mutagenesis, we show that EB2 prefers binding to microtubule lattices containing a 1:1 mixture of different nucleotides and its distinct binding specificity is conferred by amino acid substitutions at the right-hand-side interface of the EB microtubule-binding domain with tubulin. Our data are consistent with the model that all three EB paralogues sense the nucleotide state of both ß-tubulins flanking their binding site. Their different profile of preferred binding sites contributes to occupying spatially distinct domains at the temporally evolving microtubule tip structure.


Assuntos
Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Nucleotídeos/metabolismo , Tubulina (Proteína)/metabolismo , Sítios de Ligação , Humanos , Ligação Proteica , Domínios Proteicos/fisiologia , Transdução de Sinais/fisiologia
5.
J Cell Sci ; 127(Pt 24): 5179-88, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25344256

RESUMO

The kinesin KIF1C is known to regulate podosomes, actin-rich adhesion structures that remodel the extracellular matrix during physiological processes. Here, we show that KIF1C is a player in the podosome-inducing signaling cascade. Upon induction of podosome formation by protein kinase C (PKC), KIF1C translocation to the cell periphery intensifies and KIF1C accumulates both in the proximity of peripheral microtubules that show enrichment for the plus-tip-associated proteins CLASPs and around podosomes. Importantly, without CLASPs, both KIF1C trafficking and podosome formation are suppressed. Moreover, chimeric mitochondrially targeted CLASP2 recruits KIF1C, suggesting a transient CLASP-KIF1C association. We propose that CLASPs create preferred microtubule tracks for KIF1C to promote podosome induction downstream of PKC.


Assuntos
Extensões da Superfície Celular/metabolismo , Cinesinas/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Animais , Linhagem Celular , Humanos , Microtúbulos/metabolismo , Modelos Biológicos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Proteína Quinase C/metabolismo , Transporte Proteico , Ratos , Transdução de Sinais
6.
Biochem J ; 467(3): 529-36, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25740311

RESUMO

Proteins of the echinoderm microtubule (MT)-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase MT network. EML1-4 consist of Trp-Asp 40 (WD40) repeats and an N-terminal region containing a putative coiled-coil. Recurrent gene rearrangements in non-small cell lung cancer (NSCLC) fuse EML4 to anaplastic lymphoma kinase (ALK) causing expression of several oncogenic fusion variants. The fusions have constitutive ALK activity due to self-association through the EML4 coiled-coil. We have determined crystal structures of the coiled-coils from EML2 and EML4, which describe the structural basis of both EML self-association and oncogenic EML4-ALK activation. The structures reveal a trimeric oligomerization state directed by a conserved pattern of hydrophobic residues and salt bridges. We show that the trimerization domain (TD) of EML1 is necessary and sufficient for self-association. The TD is also essential for MT binding; however, this property requires an adjacent basic region. These observations prompted us to investigate MT association of EML4-ALK and EML1-ABL1 (Abelson 1) fusions in which variable portions of the EML component are present. Uniquely, EML4-ALK variant 3, which includes the TD and basic region of EML4 but none of the WD40 repeats, was localized to MTs, both when expressed recombinantly and when expressed in a patient-derived NSCLC cell line (H2228). This raises the question of whether the mislocalization of ALK activity to MTs might influence downstream signalling and malignant properties of cells. Furthermore, the structure of EML4 TD may enable the development of protein-protein interaction inhibitors targeting the trimerization interface, providing a possible avenue towards therapeutic intervention in EML4-ALK NSCLC.


Assuntos
Proteínas Associadas aos Microtúbulos/química , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Proteínas de Fusão Oncogênica/química , Proteínas de Fusão Oncogênica/metabolismo , Sequência de Aminoácidos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Sequência Conservada , Cristalografia por Raios X , Células HEK293 , Células HeLa , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Modelos Moleculares , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Proteínas de Fusão Oncogênica/genética , Domínios e Motivos de Interação entre Proteínas , Estrutura Quaternária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos
7.
Biochem Soc Trans ; 43(1): 79-83, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25619249

RESUMO

Human cells express 45 kinesins, microtubule motors that transport a variety of molecules and organelles within the cell. Many kinesins also modulate the tracks they move on by either bundling or sliding or regulating the dynamic assembly and disassembly of the microtubule polymer. In migrating cells, microtubules control the asymmetry between the front and rear of the cell by differentially regulating force generation processes and substrate adhesion. Many of these functions are mediated by kinesins, transporters as well as track modulators. In this review, we summarize the current knowledge on kinesin functions in cell migration.


Assuntos
Movimento Celular , Cinesinas/fisiologia , Adesão Celular , Humanos , Cinesinas/química , Microtúbulos/fisiologia , Transdução de Sinais
8.
Biophys J ; 104(7): 1517-28, 2013 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-23561528

RESUMO

Microtubules are cytoskeletal filaments responsible for cell morphology and intracellular organization. Their dynamical and mechanical properties are regulated through the nucleotide state of the tubulin dimers and the binding of drugs and/or microtubule-associated proteins. Interestingly, microtubule-stabilizing factors have differential effects on microtubule mechanics, but whether stabilizers have cumulative effects on mechanics or whether one effect dominates another is not clear. This is especially important for the chemotherapeutic drug Taxol, an important anticancer agent and the only known stabilizer that reduces the rigidity of microtubules. First, we ask whether Taxol will combine additively with another stabilizer or whether one stabilizer will dominate another. We call microtubules in the presence of Taxol and another stabilizer, doubly stabilized. Second, since Taxol is often added to a number of cell types for therapeutic purposes, it is important from a biomedical perspective to understand how Taxol added to these systems affects the mechanical properties in treated cells. To address these questions, we use the method of freely fluctuating filaments with our recently developed analysis technique of bootstrapping to determine the distribution of persistence lengths of a large population of microtubules treated with different stabilizers, including Taxol, guanosine-5' [(α, ß)-methyleno] triphosphate, guanosine-5'-O-(3-thiotriphosphate), tau, and MAP4. We find that combinations of these stabilizers have novel effects on the mechanical properties of microtubules.


Assuntos
Fenômenos Mecânicos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Animais , Fenômenos Biomecânicos , Análise de Fourier , Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia , Guanosina Trifosfato/análogos & derivados , Guanosina Trifosfato/farmacologia , Proteínas Associadas aos Microtúbulos/metabolismo , Distribuição Normal , Paclitaxel/farmacologia , Multimerização Proteica , Estrutura Quaternária de Proteína , Suínos , Temperatura , Proteínas tau/química , Proteínas tau/metabolismo
9.
Semin Cell Dev Biol ; 22(9): 968-74, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22001384

RESUMO

Microtubules define the architecture and internal organization of cells by positioning organelles and activities, as well as by supporting cell shape and mechanics. One of the major functions of microtubules is the control of polarized cell motility. In order to support the asymmetry of polarized cells, microtubules have to be organized asymmetrically themselves. Asymmetry in microtubule distribution and stability is regulated by multiple molecular factors, most of which are microtubule-associated proteins that locally control microtubule nucleation and dynamics. At the same time, the dynamic state of microtubules is key to the regulatory mechanisms by which microtubules regulate cell polarity, modulate cell adhesion and control force-production by the actin cytoskeleton. Here, we propose that even small alterations in microtubule dynamics can influence cell migration via several different microtubule-dependent pathways. We discuss regulatory factors, potential feedback mechanisms due to functional microtubule-actin crosstalk and implications for cancer cell motility.


Assuntos
Microtúbulos/fisiologia , Citoesqueleto de Actina/fisiologia , Movimento Celular/fisiologia , Adesões Focais/fisiologia , Humanos , Proteínas Associadas aos Microtúbulos/fisiologia
10.
Front Pharmacol ; 14: 1285779, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38155905

RESUMO

Preterm birth is the leading cause of infant morbidity and mortality. There has been an interest in developing prostaglandin F2α (PGF2α) antagonists as a new treatment for preterm birth, although much of the rationale for their use is based on studies in rodents where PGF2α initiates labour by regressing the corpus luteum and reducing systemic progesterone concentrations. How PGF2α antagonism would act in humans who do not have a fall in systemic progesterone remains unclear. One possibility, in addition to an acute stimulation of contractions, is a direct alteration of the myometrial smooth muscle cell state towards a pro-labour phenotype. In this study, we developed an immortalised myometrial cell line, MYLA, derived from myometrial tissue obtained from a pregnant, non-labouring patient, as well as a novel class of PGF2α receptor (FP) antagonist. We verified the functionality of the cell line by stimulation with PGF2α, resulting in Gαq-specific coupling and Ca2+ release, which were inhibited by FP antagonism. Compared to four published FP receptor antagonists, the novel FP antagonist N582707 was the most potent compound [Fmax 7.67 ± 0.63 (IC50 21.26 nM), AUC 7.30 ± 0.32 (IC50 50.43 nM), and frequency of Ca2+ oscillations 7.66 ± 0.41 (IC50 22.15 nM)]. RNA-sequencing of the MYLA cell line at 1, 3, 6, 12, 24, and 48 h post PGF2α treatment revealed a transforming phenotype from a fibroblastic to smooth muscle mRNA profile. PGF2α treatment increased the expression of MYLK, CALD1, and CNN1 as well as the pro-labour genes OXTR, IL6, and IL11, which were inhibited by FP antagonism. Concomitant with the inhibition of a smooth muscle, pro-labour transition, FP antagonism increased the expression of the fibroblast marker genes DCN, FBLN1, and PDGFRA. Our findings suggest that in addition to the well-described acute contractile effect, PGF2α transforms myometrial smooth muscle cells from a myofibroblast to a smooth muscle, pro-labour-like state and that the novel compound N582707 has the potential for prophylactic use in preterm labour management beyond its use as an acute tocolytic drug.

11.
Curr Biol ; 32(17): 3862-3870.e6, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-35961316

RESUMO

Intracellular transport is essential for neuronal function and survival. The most effective plus-end-directed neuronal transporter is the kinesin-3 KIF1C, which transports large secretory vesicles and endosomes.1-4 Mutations in KIF1C cause hereditary spastic paraplegia and cerebellar dysfunction in human patients.5-8 In contrast to other kinesin-3s, KIF1C is a stable dimer and a highly processive motor in its native state.9,10 Here, we establish a baseline for the single-molecule mechanics of Kif1C. We show that full-length KIF1C molecules can processively step against the load of an optical trap and reach average stall forces of 3.7 pN. Compared with kinesin-1, KIF1C has a higher propensity to slip backward under load, which results in a lower maximal single-molecule force. However, KIF1C remains attached to the microtubule while slipping backward and re-engages quickly, consistent with its super processivity. Two pathogenic mutations, P176L and R169W, that cause hereditary spastic paraplegia in humans7,8 maintain fast, processive single-molecule motility in vitro but with decreased run length and slightly increased unloaded velocity compared with the wild-type motor. Under load in an optical trap, force generation by these mutants is severely reduced. In cells, the same mutants are impaired in producing sufficient force to efficiently relocate organelles. Our results show how its mechanics supports KIF1C's role as an intracellular transporter and explain how pathogenic mutations at the microtubule-binding interface of KIF1C impair the cellular function of these long-distance transporters and result in neuronal disease.


Assuntos
Cinesinas , Paraplegia Espástica Hereditária , Humanos , Cinesinas/genética , Microtúbulos/metabolismo , Mutação , Ligação Proteica , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/metabolismo
13.
ACS Sens ; 6(10): 3696-3705, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34634204

RESUMO

The COVID-19 pandemic, and future pandemics, require diagnostic tools to track disease spread and guide the isolation of (a)symptomatic individuals. Lateral-flow diagnostics (LFDs) are rapid and of lower cost than molecular (genetic) tests, with current LFDs using antibodies as their recognition units. Herein, we develop a prototype flow-through device (related, but distinct to LFDs), utilizing N-acetyl neuraminic acid-functionalized, polymer-coated, gold nanoparticles as the detection/capture unit for SARS-COV-2, by targeting the sialic acid-binding site of the spike protein. The prototype device can give rapid results, with higher viral loads being faster than lower viral loads. The prototype's effectiveness is demonstrated using spike protein, lentiviral models, and a panel of heat-inactivated primary patient nasal swabs. The device was also shown to retain detection capability toward recombinant spike proteins from several variants (mutants) of concern. This study provides the proof of principle that glyco-lateral-flow devices could be developed to be used in the tracking monitoring of infectious agents, to complement, or as alternatives to antibody-based systems.


Assuntos
COVID-19 , Nanopartículas Metálicas , Ouro , Humanos , Pandemias , Polissacarídeos , SARS-CoV-2
14.
Curr Biol ; 17(15): 1318-25, 2007 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-17658256

RESUMO

During muscle differentiation, myoblasts elongate and fuse into syncytial myotubes [1]. An early event during this process is the remodeling of the microtubule cytoskeleton, involving disassembly of the centrosome and, crucially, the alignment of microtubules into a parallel array along the long axis of the cell [2-5]. To further our understanding on how microtubules support myogenic differentiation, we analyzed the role of EB1-related microtubule-plus-end-binding proteins. We demonstrate that EB3 [6] is specifically upregulated upon myogenic differentiation and that knockdown of EB3, but not that of EB1, prevents myoblast elongation and fusion into myotubes. EB3-depleted cells show disorganized microtubules and fail to stabilize polarized membrane protrusions. Using live-cell imaging, we show that EB3 is necessary for the regulation of microtubule dynamics and microtubule capture at the cell cortex. Expression of EB1/EB3 chimeras on an EB3-depletion background revealed that myoblast fusion depends on two specific amino acids in the calponin-like domain of EB3, whereas the interaction sites with Clip-170 and CLASPs are dispensable. Our results suggest that EB3-mediated microtubule regulation at the cell cortex is a crucial step during myogenic differentiation and might be a general mechanism in polarized cell elongation.


Assuntos
Diferenciação Celular , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Mioblastos/citologia , Sequência de Aminoácidos , Animais , Células COS , Fusão Celular , Linhagem Celular , Chlorocebus aethiops , Matriz Extracelular/metabolismo , Células HeLa , Humanos , Camundongos , Proteínas Associadas aos Microtúbulos/química , Dados de Sequência Molecular , Mioblastos/metabolismo , Estrutura Terciária de Proteína , Homologia de Sequência
15.
Front Cell Dev Biol ; 8: 621016, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33537312

RESUMO

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible adhesion molecule and a primary amine oxidase involved in immune cell trafficking. Leukocyte extravasation into tissues is mediated by adhesion molecules expressed on endothelial cells and pericytes. Pericytes play a major role in the angiogenesis and vascularization of cycling endometrium. However, the functional properties of pericytes in the human endometrium are not known. Here we show that pericytes surrounding the spiral arterioles in midluteal human endometrium constitutively express VAP-1. We first characterize these pericytes and demonstrate that knockdown of VAP-1 perturbed their biophysical properties and compromised their contractile, migratory, adhesive and clonogenic capacities. Furthermore, we show that loss of VAP-1 disrupts pericyte-uterine natural killer cell interactions in vitro. Taken together, the data not only reveal that endometrial pericytes represent a cell population with distinct biophysical and functional properties but also suggest a pivotal role for VAP-1 in regulating the recruitment of innate immune cells in human endometrium. We posit that VAP-1 could serve as a potential biomarker for pregnancy pathologies caused by a compromised perivascular environment prior to conception.

16.
ACS Cent Sci ; 6(11): 2046-2052, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33269329

RESUMO

There is an urgent need to understand the behavior of the novel coronavirus (SARS-COV-2), which is the causative agent of COVID-19, and to develop point-of-care diagnostics. Here, a glyconanoparticle platform is used to discover that N-acetyl neuraminic acid has affinity toward the SARS-COV-2 spike glycoprotein, demonstrating its glycan-binding function. Optimization of the particle size and coating enabled detection of the spike glycoprotein in lateral flow and showed selectivity over the SARS-COV-1 spike protein. Using a virus-like particle and a pseudotyped lentivirus model, paper-based lateral flow detection was demonstrated in under 30 min, showing the potential of this system as a low-cost detection platform.

17.
Biochem Soc Trans ; 37(Pt 5): 1007-13, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19754441

RESUMO

Proper regulation of MT (microtubule) dynamics is essential for various vital processes, including the segregation of chromosomes, directional cell migration and differentiation. MT assembly and disassembly is modulated by a complex network of intracellular factors that co-operate or antagonize each other, are highly regulated in space and time and are thus attuned to the cell cycle and differentiation processes. While we only begin to appreciate how the concerted action of MT stabilizers and destabilizers shapes different MT patterns, a clear picture of how individual factors affect the MT structure is emerging. In this paper, we review the current knowledge about proteins that modulate MT dynamic instability.


Assuntos
Microtúbulos/química , Microtúbulos/metabolismo , Conformação Proteica , Animais , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Tubulina (Proteína)/metabolismo
18.
Mol Biol Cell ; 17(2): 907-16, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16339079

RESUMO

Conventional kinesin is a ubiquitous organelle transporter that moves cargo toward the plus-ends of microtubules. In addition, several in vitro studies indicated a role of conventional kinesin in cross-bridging and sliding microtubules, but in vivo evidence for such a role is missing. In this study, we show that conventional kinesin mediates microtubule-microtubule interactions in the model fungus Ustilago maydis. Live cell imaging and ultrastructural analysis of various mutants in Kin1 revealed that this kinesin-1 motor is required for efficient microtubule bundling and participates in microtubule bending in vivo. High levels of Kin1 led to increased microtubule bending, whereas a rigor-mutation in the motor head suppressed all microtubule motility and promoted strong microtubule bundling, indicating that kinesin can form cross-bridges between microtubules in living cells. This effect required a conserved region in the C terminus of Kin1, which was shown to bind microtubules in vitro. In addition, a fusion protein of yellow fluorescent protein and the Kin1tail localized to microtubule bundles, further supporting the idea that a conserved microtubule binding activity in the tail of conventional kinesins mediates microtubule-microtubule interactions in vivo.


Assuntos
Proteínas Fúngicas/fisiologia , Cinesinas/fisiologia , Microtúbulos/metabolismo , Ustilago/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Transporte Biológico , Sequência Conservada , Proteínas Fúngicas/genética , Cinesinas/genética , Microtúbulos/fisiologia , Microtúbulos/ultraestrutura , Dados de Sequência Molecular , Mutação , Ligação Proteica , Proteínas Recombinantes de Fusão/análise , Alinhamento de Sequência , Deleção de Sequência , Ustilago/química , Ustilago/citologia
19.
Essays Biochem ; 63(5): 509-520, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31358621

RESUMO

Directed cell migration is critical for embryogenesis and organ development, wound healing and the immune response. Microtubules are dynamic polymers that control directional migration through a number of coordinated processes: microtubules are the tracks for long-distance intracellular transport, crucial for delivery of new membrane components and signalling molecules to the leading edge of a migrating cell and the recycling of adhesion receptors. Microtubules act as force generators and compressive elements to support sustained cell protrusions. The assembly and disassembly of microtubules is coupled to Rho GTPase signalling, thereby controlling actin polymerisation, myosin-driven contractility and the turnover of cellular adhesions locally. Cross-talk of actin and microtubule dynamics is mediated through a number of common binding proteins and regulators. Furthermore, cortical microtubule capture sites are physically linked to focal adhesions, facilitating the delivery of secretory vesicles and efficient cross-talk. Here we summarise the diverse functions of microtubules during cell migration, aiming to show how they contribute to the spatially and temporally coordinated sequence of events that permit efficient, directional and persistent migration.


Assuntos
Movimento Celular/fisiologia , Microtúbulos/metabolismo , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Adesão Celular/fisiologia , Adesões Focais/metabolismo , Humanos , Transdução de Sinais/fisiologia , Proteínas rho de Ligação ao GTP/metabolismo
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