Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
J Cell Sci ; 135(7)2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35394045

RESUMO

Altered endocytosis and vesicular trafficking are major players during tumorigenesis. Flotillin overexpression, a feature observed in many invasive tumors and identified as a marker of poor prognosis, induces a deregulated endocytic and trafficking pathway called upregulated flotillin-induced trafficking (UFIT). Here, we found that in non-tumoral mammary epithelial cells, induction of the UFIT pathway promotes epithelial-to-mesenchymal transition (EMT) and accelerates the endocytosis of several transmembrane receptors, including AXL, in flotillin-positive late endosomes. AXL overexpression, frequently observed in cancer cells, is linked to EMT and metastasis formation. In flotillin-overexpressing non-tumoral mammary epithelial cells and in invasive breast carcinoma cells, we found that the UFIT pathway-mediated AXL endocytosis allows its stabilization and depends on sphingosine kinase 2, a lipid kinase recruited in flotillin-rich plasma membrane domains and endosomes. Thus, the deregulation of vesicular trafficking following flotillin upregulation, and through sphingosine kinase 2, emerges as a new mechanism of AXL overexpression and EMT-inducing signaling pathway activation.


Assuntos
Neoplasias da Mama , Transição Epitelial-Mesenquimal , Proteínas de Membrana , Fosfotransferases (Aceptor do Grupo Álcool) , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina Quinases , Linhagem Celular Tumoral , Feminino , Humanos , Proteínas de Membrana/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Tirosina Quinase Axl
2.
Cancer Metastasis Rev ; 39(2): 361-374, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32297092

RESUMO

Flotillins 1 and 2 are two ubiquitous, highly conserved homologous proteins that assemble to form heterotetramers at the cytoplasmic face of the plasma membrane in cholesterol- and sphingolipid-enriched domains. Flotillin heterotetramers can assemble into large oligomers to form molecular scaffolds that regulate the clustering of at the plasma membrane and activity of several receptors. Moreover, flotillins are upregulated in many invasive carcinomas and also in sarcoma, and this is associated with poor prognosis and metastasis formation. When upregulated, flotillins promote plasma membrane invagination and induce an endocytic pathway that allows the targeting of cargo proteins in the late endosomal compartment in which flotillins accumulate. These late endosomes are not degradative, and participate in the recycling and secretion of protein cargos. The cargos of this Upregulated Flotillin-Induced Trafficking (UFIT) pathway include molecules involved in signaling, adhesion, and extracellular matrix remodeling, thus favoring the acquisition of an invasive cellular behavior leading to metastasis formation. Thus, flotillin presence from the plasma membrane to the late endosomal compartment influences the activity, and even modifies the trafficking and fate of key protein cargos, favoring the development of diseases, for instance tumors. This review summarizes the current knowledge on flotillins and their role in cancer development focusing on their function in cellular membrane remodeling and vesicular trafficking regulation.


Assuntos
Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Animais , Carcinogênese , Membrana Celular/metabolismo , Humanos , Microdomínios da Membrana/metabolismo , Microdomínios da Membrana/patologia , Proteínas de Membrana/biossíntese , Neoplasias/patologia
3.
J Cell Sci ; 131(17)2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30111578

RESUMO

Tumor cell invasion and metastasis formation are the major cause of death in cancer patients. These processes rely on extracellular matrix (ECM) degradation mediated by organelles termed invadopodia, to which the transmembrane matrix metalloproteinase MT1-MMP (also known as MMP14) is delivered from its reservoir, the RAB7-containing endolysosomes. How MT1-MMP is targeted to endolysosomes remains to be elucidated. Flotillin-1 and -2 are upregulated in many invasive cancers. Here, we show that flotillin upregulation triggers a general mechanism, common to carcinoma and sarcoma, which promotes RAB5-dependent MT1-MMP endocytosis and its delivery to RAB7-positive endolysosomal reservoirs. Conversely, flotillin knockdown in invasive cancer cells greatly reduces MT1-MMP accumulation in endolysosomes, its subsequent exocytosis at invadopodia, ECM degradation and cell invasion. Our results demonstrate that flotillin upregulation is necessary and sufficient to promote epithelial and mesenchymal cancer cell invasion and ECM degradation by controlling MT1-MMP endocytosis and delivery to the endolysosomal recycling compartment.


Assuntos
Endossomos/metabolismo , Lisossomos/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Linhagem Celular Tumoral , Endocitose , Endossomos/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Humanos , Lisossomos/genética , Metaloproteinase 14 da Matriz/genética , Proteínas de Membrana/genética , Invasividade Neoplásica , Neoplasias/genética , Neoplasias/patologia , Podossomos/genética , Podossomos/metabolismo , Transporte Proteico , Regulação para Cima , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab5 de Ligação ao GTP/genética , Proteínas rab5 de Ligação ao GTP/metabolismo , proteínas de unión al GTP Rab7
4.
J Cell Sci ; 127(Pt 24): 5139-47, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25413346

RESUMO

Flotillin 1 and 2 are ubiquitous and highly conserved proteins. They were initially discovered in 1997 as being associated with specific caveolin-independent cholesterol- and glycosphingolipid-enriched membrane microdomains and as being expressed during axon regeneration. Flotillins have a role in a large number of physiopathological processes, mainly through their function in membrane receptor clustering and in the regulation of clathrin-independent endocytosis. In this Commentary, we summarize the research performed so far on the role of flotillins in cell-cell adhesion. Recent studies have demonstrated that flotillins directly regulate the formation of cadherin complexes. Indeed, flotillin microdomains are required for the dynamic association and stabilization of cadherins at cell-cell junctions and also for cadherin signaling. Moreover, because flotillins regulate endocytosis and also the actin cytoskeleton, they could have an indirect role in the assembly and stabilization of cadherin complexes. Because it has also recently been shown that flotillins are overexpressed during neurodegenerative diseases and in human cancers, where their upregulation is associated with metastasis formation and poor prognosis, understanding to what extent flotillin upregulation participates in the development of such pathologies is thus of particular interest, as well as how, at the molecular level, it might affect cell adhesion processes.


Assuntos
Fenômenos Fisiológicos Celulares , Doença , Proteínas de Membrana/metabolismo , Caderinas/metabolismo , Adesão Celular , Humanos , Proteínas de Membrana/química , Modelos Biológicos
5.
J Cell Sci ; 126(Pt 22): 5293-304, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24046456

RESUMO

Cadherins are essential in many fundamental processes and assemble at regions of cell-cell contact in large macromolecular complexes named adherens junctions. We have identified flotillin 1 and 2 as new partners of the cadherin complexes. We show that flotillins are localised at cell-cell junctions (CCJs) in a cadherin-dependent manner. Flotillins and cadherins are constitutively associated at the plasma membrane and their colocalisation at CCJ increases with CCJ maturation. Using three-dimensional structured illumination super-resolution microscopy, we found that cadherin and flotillin complexes are associated with F-actin bundles at CCJs. The knockdown of flotillins dramatically affected N- and E-cadherin recruitment at CCJs in mesenchymal and epithelial cell types and perturbed CCJ integrity and functionality. Moreover, we determined that flotillins are required for cadherin association with GM1-containing plasma membrane microdomains. This allows p120 catenin binding to the cadherin complex and its stabilization at CCJs. Altogether, these data demonstrate that flotillin microdomains are required for cadherin stabilization at CCJs and for the formation of functional CCJs.


Assuntos
Caderinas/metabolismo , Junções Intercelulares/genética , Proteínas de Membrana/metabolismo , Caderinas/genética , Cateninas/metabolismo , Membrana Celular/metabolismo , Técnicas de Silenciamento de Genes , Células HCT116 , Humanos , Junções Intercelulares/metabolismo , Células MCF-7 , Proteínas de Membrana/genética , Estrutura Terciária de Proteína , Proteínas Ativadoras de Esfingolipídeos/metabolismo , delta Catenina
6.
J Cell Biol ; 212(2): 199-217, 2016 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-26783302

RESUMO

Collective cell migration (CCM) is essential for organism development, wound healing, and metastatic transition, the primary cause of cancer-related death, and it involves cell-cell adhesion molecules of the cadherin family. Increased P-cadherin expression levels are correlated with tumor aggressiveness in carcinoma and aggressive sarcoma; however, how P-cadherin promotes tumor malignancy remains unknown. Here, using integrated cell biology and biophysical approaches, we determined that P-cadherin specifically induces polarization and CCM through an increase in the strength and anisotropy of mechanical forces. We show that this mechanical regulation is mediated by the P-cadherin/ß-PIX/Cdc42 axis; P-cadherin specifically activates Cdc42 through ß-PIX, which is specifically recruited at cell-cell contacts upon CCM. This mechanism of cell polarization and migration is absent in cells expressing E- or R-cadherin. Thus, we identify a specific role of P-cadherin through ß-PIX-mediated Cdc42 activation in the regulation of cell polarity and force anisotropy that drives CCM.


Assuntos
Caderinas/metabolismo , Movimento Celular , Proteína cdc42 de Ligação ao GTP/metabolismo , Animais , Fenômenos Biomecânicos , Polaridade Celular , Células Cultivadas , Camundongos , Mioblastos/citologia , Mioblastos/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo
7.
Mol Biol Cell ; 27(17): 2653-61, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27413008

RESUMO

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of skeletal muscle origin in children and adolescents. Among RMS subtypes, alveolar rhabdomyosarcoma (ARMS), which is characterized by the presence of the PAX3-FOXO1A or PAX7-FOXO1A chimeric oncogenic transcription factor, is associated with poor prognosis and a strong risk of metastasis compared with the embryonal subtype (ERMS). To identify molecular pathways involved in ARMS aggressiveness, we first characterized the migratory behavior of cell lines derived from ARMS and ERMS biopsies using a three-dimensional spheroid cell invasion assay. ARMS cells were more invasive than ERMS cells and adopted an ellipsoidal morphology to efficiently invade the extracellular matrix. Moreover, the invasive potential of ARMS cells depended on ROCK activity, which is regulated by the GTPase RhoE. Specifically, RhoE expression was low in ARMS biopsies, and its overexpression in ARMS cells reduced their invasion potential. Conversely, ARHGAP25, a GTPase-activating protein for Rac, was up-regulated in ARMS biopsies. Moreover, we found that ARHGAP25 inhibits Rac activity downstream of ROCKII and is required for ARMS cell invasion. Our results indicate that the RhoE/ROCK/ARHGAP25 signaling pathway promotes ARMS invasive potential and identify these proteins as potential therapeutic targets for ARMS treatment.


Assuntos
Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismo , Diferenciação Celular , Linhagem Celular , Movimento Celular/genética , Movimento Celular/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Músculo Esquelético/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Rabdomiossarcoma , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/metabolismo , Transdução de Sinais/genética , Proteínas rac de Ligação ao GTP/antagonistas & inibidores , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA