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1.
EMBO Rep ; 21(6): e49234, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32270908

RESUMO

Centrosome amplification is a hallmark of cancer, and centrosome clustering is essential for cancer cell survival. The mitotic kinesin HSET is an essential contributor to this process. Recent studies have highlighted novel functions for intraflagellar transport (IFT) proteins in regulating motors and mitotic processes. Here, using siRNA knock-down of various IFT proteins or AID-inducible degradation of endogenous IFT88 in combination with small-molecule inhibition of HSET, we show that IFT proteins together with HSET are required for efficient centrosome clustering. We identify a direct interaction between the kinesin HSET and IFT proteins, and we define how IFT proteins contribute to clustering dynamics during mitosis using high-resolution live imaging of centrosomes. Finally, we demonstrate the requirement of IFT88 for efficient centrosome clustering in a variety of cancer cell lines naturally harboring supernumerary centrosomes and its importance for cancer cell proliferation. Overall, our data unravel a novel role for the IFT machinery in centrosome clustering during mitosis in cells harboring supernumerary centrosomes.


Assuntos
Proteínas de Transporte , Centrossomo , Proteínas de Transporte/genética , Centrossomo/metabolismo , Análise por Conglomerados , Cinesinas/genética , Cinesinas/metabolismo , Mitose/genética
2.
J Cell Biol ; 178(1): 23-30, 2007 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-17606864

RESUMO

In addition to its role in controlling cell cycle progression, the tumor suppressor protein p53 can also affect other cellular functions such as cell migration. In this study, we show that p53 deficiency in mouse embryonic fibroblasts cultured in three-dimensional matrices induces a switch from an elongated spindle morphology to a markedly spherical and flexible one associated with highly dynamic membrane blebs. These rounded, motile cells exhibit amoeboid-like movement and have considerably increased invasive properties. The morphological transition requires the RhoA-ROCK (Rho-associated coil-containing protein kinase) pathway and is prevented by RhoE. A similar p53-mediated transition is observed in melanoma A375P cancer cells. Our data suggest that genetic alterations of p53 in tumors are sufficient to promote motility and invasion, thereby contributing to metastasis.


Assuntos
Movimento Celular/fisiologia , Matriz Extracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Invasividade Neoplásica , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Supressora de Tumor p53/deficiência , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Forma Celular/fisiologia , Células Cultivadas , Colágeno/metabolismo , Combinação de Medicamentos , Eletroporação , Embrião de Mamíferos , Fibroblastos/citologia , Fibroblastos/metabolismo , Deleção de Genes , Laminina/metabolismo , Camundongos , Proteoglicanas/metabolismo , Transfecção , Proteína Supressora de Tumor p53/genética , Quinases Associadas a rho , Proteína rhoA de Ligação ao GTP/análise
3.
Nature ; 426(6966): 555-9, 2003 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-14654840

RESUMO

Drosophila thoracic mechanosensory bristles originate from cells that are singled out from 'proneural' groups of competent epithelial cells. Neural competence is restricted to individual sensory organ precursors (SOPs) by Delta/Notch-mediated 'lateral inhibition', whereas other cells in the proneural field adopt an epidermal fate. The precursors of the large macrochaetes differentiate separately from individual proneural clusters that comprise about 20-30 cells or as heterochronic pairs from groups of more than 100 cells, whereas the precursors of the small regularly spaced microchaetes emerge from even larger proneural fields. This indicates that lateral inhibition might act over several cell diameters; it was difficult to reconcile with the fact that the inhibitory ligand Delta is membrane-bound until the observation that SOPs frequently extend thin processes offered an attractive hypothesis. Here we show that the extension of these planar filopodia--a common attribute of wing imaginal disc cells--is promoted by Delta and that their experimental suppression reduces Notch signalling in distant cells and increases bristle density in large proneural groups, showing that these membrane specializations mediate long-range lateral inhibition.


Assuntos
Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Proteínas de Membrana/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Pseudópodes/metabolismo , Animais , Diferenciação Celular , Proteínas do Citoesqueleto , Proteínas de Drosophila , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Peptídeos e Proteínas de Sinalização Intracelular , Ligantes , Proteínas de Membrana/genética , Fenótipo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Receptores Notch , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/metabolismo
4.
Sci Rep ; 9(1): 10311, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31312011

RESUMO

To build and maintain mitotic spindle architecture, molecular motors exert spatially regulated forces on microtubules (MT) minus-ends. This spatial regulation is required to allow proper chromosomes alignment through the organization of kinetochore fibers (k-fibers). NuMA was recently shown to target dynactin to MT minus-ends and thus to spatially regulate dynein activity. However, given that k-fibers are embedded in the spindle, our understanding of the machinery involved in the targeting of proteins to their minus-ends remains limited. Intraflagellar transport (IFT) proteins were primarily studied for their ciliary roles but they also emerged as key regulators of cell division. Taking advantage of MT laser ablation, we show here that IFT88 concentrates at k-fibers minus-ends and is required for their re-anchoring into spindles by controlling NuMA accumulation. Indeed, IFT88 interacts with NuMA and is required for its enrichment at newly generated k-fibers minus-ends. Combining nocodazole washout experiments and IFT88 depletion, we further show that IFT88 is required for the reorganization of k-fibers into spindles and thus for efficient chromosomes alignment in mitosis. Overall, we propose that IFT88 could serve as a mitotic MT minus-end adaptor to concentrate NuMA at minus-ends thus facilitating k-fibers incorporation into the main spindle.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Fuso Acromático/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular , Células HCT116 , Humanos , Terapia a Laser , Nocodazol/farmacologia , Fuso Acromático/efeitos dos fármacos , Sus scrofa
5.
Methods Enzymol ; 439: 413-24, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18374180

RESUMO

Cell migration plays a key role both in physiological conditions, such as tissue repair or embryonic development, and in pathological processes, including tumor metastasis. Understanding the mechanisms that allow cancer cells to invade tissues during metastasis requires studying their ability to migrate. While spectacular, the movements observed in cells growing on two-dimensional supports are likely only to represent a deformation of the physiological migratory behavior. In contrast, the analysis of cell migration on a support, which resembles the three-dimensional (3D) extracellular matrix, provides a more pertinent model of physiological relevance. This chapter provides protocols to assay the ability of cells to migrate or to invade a 3D matrix and to analyze their phenotypes. The invasion assay allows the quantification of tumor cell invasiveness, and the 3D migration assay permits the visual observation of the movements and morphology of migrating cells. This chapter also describes a method to examine the localization of different markers during 3D migration. Because Rho GTPases are clearly involved in migration and invasion, a protocol is supplied to evaluate their activation during cell migration. These techniques are especially suitable to elucidate the type of motility in a 3D matrix, particularly to discriminate between two different modes of migration adopted by cancer cells: blebbing versus elongation. Indeed, the way a cell moves may have important consequences for its invasiveness, as, for example, cancer cells adopt a rounded blebbing movement when deficient in p53.


Assuntos
Ensaios de Migração Celular/métodos , Movimento Celular/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Proteínas rho de Ligação ao GTP/fisiologia , Movimento Celular/efeitos dos fármacos , Imunofluorescência , Proteínas de Fluorescência Verde/genética , Transfecção , Proteínas rho de Ligação ao GTP/análise
6.
Cancer Res ; 65(23): 10872-80, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16322234

RESUMO

We showed previously that the spleen tyrosine kinase Syk is expressed by mammary epithelial cells and that it suppresses malignant growth of breast cancer cells. The exact molecular mechanism of its tumor-suppressive activity remains, however, to be identified. Here, we show that Syk colocalizes and copurifies with the centrosomal component gamma-tubulin and exhibits a catalytic activity within the centrosomes. Moreover, its centrosomal localization depends on its intact kinase activity. Centrosomal Syk expression is persistent in interphase but promptly drops during mitosis, obviously resulting from its ubiquitinylation and proteasomal degradation. Conversely, unrestrained exogenous expression of a fluorescently tagged Discosoma sp. red fluorescent protein (DsRed)-Syk chimera engenders abnormal cell division and cell death. Transient DsRed-Syk overexpression triggers an abrupt cell death lacking hallmarks of classic apoptosis but reminiscent of mitotic catastrophe. Surviving stable DsRed-Syk-transfected cells exhibit multipolar mitotic spindles and contain multiple abnormally sized nuclei and supernumerary centrosomes, revealing anomalous cell division. Taken together, these results show that Syk is a novel centrosomal kinase that negatively affects cell division. Its expression is strictly controlled in a spatiotemporal manner, and centrosomal Syk levels need to decline to allow customary progression of mitosis.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Centrossomo/enzimologia , Mitose/fisiologia , Proteína-Tirosina Quinase ZAP-70/metabolismo , Animais , Neoplasias da Mama/metabolismo , Células COS , Catálise , Linhagem Celular Tumoral , Chlorocebus aethiops , Humanos , Células Jurkat , Complexo de Endopeptidases do Proteassoma/metabolismo , Transfecção , Tubulina (Proteína)/metabolismo , Ubiquitina/metabolismo , Proteína-Tirosina Quinase ZAP-70/genética
7.
Nat Commun ; 8(1): 1928, 2017 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-29203870

RESUMO

Cytokinesis mediates the physical separation of dividing cells and, in 3D epithelia, provides a spatial landmark for lumen formation. Here, we unravel an unexpected role in cytokinesis for proteins of the intraflagellar transport (IFT) machinery, initially characterized for their ciliary role and their link to polycystic kidney disease. Using 2D and 3D cultures of renal cells, we show that IFT proteins are required to correctly shape the central spindle, to control symmetric cleavage furrow ingression and to ensure central lumen positioning. Mechanistically, IFT88 directly interacts with the kinesin MKLP2 and is essential for the correct relocalization of the Aurora B/MKLP2 complex to the central spindle. IFT88 is thus required for proper centralspindlin distribution and central spindle microtubule organization. Overall, this work unravels a novel non-ciliary mechanism for IFT proteins at the central spindle, which could contribute to kidney cyst formation by affecting lumen positioning.


Assuntos
Aurora Quinase B/metabolismo , Citocinese/genética , Cinesinas/metabolismo , Microtúbulos/metabolismo , Fuso Acromático/metabolismo , Proteínas Supressoras de Tumor/genética , Animais , Células Cultivadas , Células HCT116 , Células HeLa , Humanos , Rim/citologia , Túbulos Renais/citologia , Doenças Renais Policísticas/genética , Sus scrofa , Proteínas Supressoras de Tumor/metabolismo
9.
PLoS One ; 12(2): e0172125, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28212429

RESUMO

The TP53 gene plays essential roles in cancer. Conventionally, wild type (WT) p53 is thought to prevent cancer development and metastasis formation, while mutant p53 has transforming abilities. However, clinical studies failed to establish p53 mutation status as an unequivocal predictive or prognostic factor of cancer progression. The recent discovery of p53 isoforms that can differentially regulate cell cycle arrest and apoptosis suggests that their expression, rather than p53 mutations, could be a more clinically relevant biomarker in patients with cancer. In this study, we show that the p53 isoform delta133p53ß is involved in regulating the apoptotic response in colorectal cancer cell lines. We first demonstrate delta133p53ß association with the small GTPase RhoB, a well-described anti-apoptotic protein. We then show that, by inhibiting RhoB activity, delta133p53ß protects cells from camptothecin-induced apoptosis. Moreover, we found that high delta133p53 mRNA expression levels are correlated with higher risk of recurrence in a series of patients with locally advanced rectal cancer (n = 36). Our findings describe how a WT TP53 isoform can act as an oncogene and add a new layer to the already complex p53 signaling network.


Assuntos
Apoptose , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Proteína Supressora de Tumor p53/metabolismo , Proteína rhoB de Ligação ao GTP/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , Ligação Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Supressora de Tumor p53/genética
10.
Elife ; 52016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27630122

RESUMO

TP53 is conventionally thought to prevent cancer formation and progression to metastasis, while mutant TP53 has transforming activities. However, in the clinic, TP53 mutation status does not accurately predict cancer progression. Here we report, based on clinical analysis corroborated with experimental data, that the p53 isoform Δ133p53ß promotes cancer cell invasion, regardless of TP53 mutation status. Δ133p53ß increases risk of cancer recurrence and death in breast cancer patients. Furthermore Δ133p53ß is critical to define invasiveness in a panel of breast and colon cell lines, expressing WT or mutant TP53. Endogenous mutant Δ133p53ß depletion prevents invasiveness without affecting mutant full-length p53 protein expression. Mechanistically WT and mutant Δ133p53ß induces EMT. Our findings provide explanations to 2 long-lasting and important clinical conundrums: how WT TP53 can promote cancer cell invasion and reciprocally why mutant TP53 gene does not systematically induce cancer progression.


Assuntos
Neoplasias da Mama/genética , Neoplasias do Colo/genética , Recidiva Local de Neoplasia/genética , Proteína Supressora de Tumor p53/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias do Colo/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Invasividade Neoplásica/genética , Recidiva Local de Neoplasia/patologia , Isoformas de Proteínas/genética , Proteína Supressora de Tumor p53/biossíntese
11.
Mol Nutr Food Res ; 58(6): 1349-64, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24668798

RESUMO

SCOPE: The aim was to investigate the effect of postprandial triglyceride-rich lipoproteins (TRLs) with different fatty acid compositions on human coronary artery smooth muscle cell (hCASMC) invasion and to identify the molecular pathways involved. METHODS AND RESULTS: TRLs were isolated from the plasma of healthy volunteers after the ingestion of single meals enriched in MUFAs, saturated fatty acids (SFAs), or PUFAs. hCASMC invasion was analyzed using transwell chambers with Matrigel. TRLs-SFAs provoked the highest invasion, followed by TRLs-MUFAs and TRLs-PUFAs. Inhibition studies with Orlistat showed that invasion was dependent on the fatty acid composition of the TRLs. Fatty acids incorporated into the cell membranes strongly associated with cell invasion. Pull-down assays showed that TRLs-SFAs were able to increase Rac1 activity via inhibition of RhoA-dependent signaling. Chemical inhibition and siRNA studies showed that Rac1, PI3k, JNK, and MMP2 regulates TRL-SFA-induced hCASMC invasion. CONCLUSION: We demonstrate for the first time that TRLs induce hCASMCs invasion in a fatty acid dependent manner. This effect in TRLs-SFAs is mediated by the PI3k-Rac1-JNK, RhoA, and Rac1-MMP2 pathways. The ingestion of MUFA, compared to other dietary fatty acids such as SFA, could be considered as a nutritional strategy to reduce the atherosclerotic plaque formation.


Assuntos
Vasos Coronários/citologia , Lipoproteínas/sangue , Miócitos de Músculo Liso/efeitos dos fármacos , Período Pós-Prandial/efeitos dos fármacos , Triglicerídeos/sangue , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Células Cultivadas , Criança , Gorduras na Dieta/administração & dosagem , Ácidos Graxos/administração & dosagem , Ácidos Graxos Monoinsaturados/administração & dosagem , Ácidos Graxos Insaturados/administração & dosagem , Feminino , Voluntários Saudáveis , Humanos , Modelos Lineares , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Período Pós-Prandial/fisiologia , Pseudópodes/efeitos dos fármacos , Pseudópodes/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
12.
PLoS One ; 7(11): e48344, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23144867

RESUMO

Rho GTPases are key regulators of tumour cell invasion and therefore constitute attractive targets for the design of anticancer agents. Several strategies have been developed to modulate their increased activities during cancer progression. Interestingly, none of these approaches took into account the existence of the well-known antagonistic relationship between RhoA and Rac1. In this study, we first compared the invasiveness of a collection of colorectal cancer cell lines with their RhoA, Rac1 and Cdc42 activities. A marked decrease of active Cdc42 and Rac1 correlated with the high invasive potential of the cell lines established from metastatic sites of colorectal adenocarcinoma (LoVo, SKCo1, SW620 and CoLo205). Conversely, no correlation between RhoA activity and invasiveness was detected, whereas the activity of its kinase effector ROCK was higher in cancer cell lines with a more invasive phenotype. In addition, invasiveness in these colon cancer cell lines was correlated with a typical round and blebbing morphology. We then tested whether treatment with PDGF to restore Cdc42 and Rac1 activities and/or with Y27632, a chemical inhibitor of ROCK, could decrease the invasiveness of SW620 cells. The association of both treatments substantially decreased the invasive potential of SW620 cells and this effect was accompanied by loss of membrane blebbing, restoration of a more elongated cell morphology and re-establishment of E-cadherin-dependent adherens junctions. This study paves the road to the development of therapeutic strategies in which different Rho GTPase modulators are combined to modulate the cross-talk between Rho GTPases and their specific input in metastatic progression.


Assuntos
Movimento Celular , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , Fatores de Despolimerização de Actina/metabolismo , Amidas/farmacologia , Caderinas/metabolismo , Linhagem Celular Tumoral , Membrana Celular , Forma Celular , Humanos , Microscopia de Polarização , Fosforilação , Fator de Crescimento Derivado de Plaquetas/farmacologia , Fator de Crescimento Derivado de Plaquetas/fisiologia , Processamento de Proteína Pós-Traducional , Piridinas/farmacologia , Imagem com Lapso de Tempo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
13.
PLoS One ; 7(2): e32204, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22363817

RESUMO

The microenvironment of a tumor can influence both the morphology and the behavior of cancer cells which, in turn, can rapidly adapt to environmental changes. Increasing evidence points to the involvement of amoeboid cell migration and thus of cell blebbing in the metastatic process; however, the cues that promote amoeboid cell behavior in physiological and pathological conditions have not yet been clearly identified. Plasminogen Activator Inhibitor type-1 (PAI-1) is found in high amount in the microenvironment of aggressive tumors and is considered as an independent marker of bad prognosis. Here we show by immunoblotting, activity assay and immunofluorescence that, in SW620 human colorectal cancer cells, matrix-associated PAI-1 plays a role in the cell behavior needed for amoeboid migration by maintaining cell blebbing, localizing PDK1 and ROCK1 at the cell membrane and maintaining the RhoA/ROCK1/MLC-P pathway activation. The results obtained by modeling PAI-1 deposition around tumors indicate that matrix-bound PAI-1 is heterogeneously distributed at the tumor periphery and that, at certain spots, the elevated concentrations of matrix-bound PAI-1 needed for cancer cells to undergo the mesenchymal-amoeboid transition can be observed. Matrix-bound PAI-1, as a matricellular protein, could thus represent one of the physiopathological requirements to support metastatic formation.


Assuntos
Extensões da Superfície Celular/efeitos dos fármacos , Extensões da Superfície Celular/metabolismo , Matriz Extracelular/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Simulação por Computador , Ativação Enzimática/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Humanos , Proteínas Imobilizadas/farmacologia , Mesoderma/efeitos dos fármacos , Mesoderma/patologia , Modelos Biológicos , Inibidor 1 de Ativador de Plasminogênio/farmacologia , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/farmacologia
14.
J Cell Sci ; 117(Pt 26): 6355-64, 2004 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-15561766

RESUMO

Cell migration is an essential function in various physiological processes, including tissue repair and tumour invasion. Repair of tissue damage requires the recruitment of fibroblasts to sites of tissue injury, which is mediated in part by the cytokine tumour necrosis factor alpha (TNFalpha). As dynamic rearrangements of actin cytoskeleton control cell locomotion, this implicates that TNFalpha is a potent coordinator of cellular actin changes. We have investigated the role of TNFalpha in regulating the cortical actin-containing structures essential for cell locomotion called filopodia. Kinetic analysis of TNFalpha-treated mouse embryonic fibroblasts (MEFs) revealed a dual effect on filopodia formation: a rapid and transient induction mediated by Cdc42 GTPase that is then counteracted by a subsequent sustained inhibition requiring activation of the mitogen-activated protein kinase p38 but not Cdc42 activity. This inhibition also involves the tumour suppressor p53, given that it is activated in response to TNFalpha following the same time course as the decrease of filopodia formation. This functional activation of p53, measured by transcription induction of its target p21WAF1(p21), is also associated with p38 kinase-dependent phosphorylation of p53 at serine 18. Furthermore, TNFalpha did not inhibit filopodia formation in MEFs treated with the transcription inhibitor actinomycin D, in p53-deficient MEFs, or MEFs expressing p53 mutants H273 or H175, which supports a role for the transcriptional activity of p53 in mediating TNFalpha-dependent filopodia inhibition. Our data delineate a novel inhibitory pathway in which TNFalpha prevents filopodia formation and cell migration through the activation of the mitogen-activated protein kinase (MAPK) p38, which in turn activates p53. This shows that TNFalpha on its own initiates antagonistic signals that modulate events linked to cell migration.


Assuntos
Pseudópodes/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Células Cultivadas , Embrião de Mamíferos , Ativação Enzimática , Fibroblastos/efeitos dos fármacos , Cinética , Camundongos , Fosforilação , Pseudópodes/fisiologia
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