45 results on '"Ramel, D."'
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2. La integración de datos geológicos, hidrogeológicos y geofísicos con el fin de identificar los recursos de aguas subterráneas en zonas de basamento granítico (Macizo de Guéra, Chad)
- Author
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Nouradine, H., primary, Schamper, C., additional, Valdes, D., additional, Moussa, I., additional, Ramel, D., additional, and Plagnes, V., additional
- Published
- 2024
- Full Text
- View/download PDF
3. Best Participatory Practices in Mangrove Conservation Management: The Case in the Mangrove Rehabilitation Program in the Fishing Villages in the Philippines
- Author
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Ramel D. Tomaquin
- Subjects
General Medicine - Abstract
The mangrove conservation program is one of the measures to address climate change at the village or community level and is the most effective and sustainable. For it entails a community participatory approach and is anchored on the participation of the private sector, and people’s organizations. Bayabas, a coastal municipality of Surigao del Sur, in the Philippines with the communities Cabugo, Magobawok, Belete, and La Paz, the sites of the study, has a robust mangrove conservation program. The study used mixed methods of survey, ethnographic, and observation/case study methods which capture the organizational culture of the sites. The findings of the study include the following: The Mangrove Conservation sites were established in response to the significant provisions of the Local Government Code of 1991 bearing on Environmental Conservation duly supported by an Ordinance of the LGU of Bayabas. The operation of the Mangrove Conservation sites was being assisted by the People’s Organization (PO) which is also a quasi-cooperative for fishers. The POs were established by a joint effort of the PFAR/BFAR and the LGU of Bayabas. Sagip Wakatan, the Mangrove Conservation Program of the LGU of Bayabas was anchored on food security, sustainable development, people’s empowerment, eco-tourism, and the response to climate change initiatives at the grassroots levels. Livelihood integration is one of the most important features of the Mangrove Conservation Program and was directly channeled into the four (4) People’s Organizations (POs). The fishers across four (4) sites are active enough in their participation in the Mangrove Conservation.
- Published
- 2023
4. Healing Practices of the Spiritual Folk Healers of Tandag: A Construct of their Social Reality and Mysticism
- Author
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Ramel D. Tomaquin
- Abstract
The paper discusses the rituals performed by the diviner or spiritual healer in curing the clients. It involves prayers, chants and elaborate ceremonies addressed to the supreme deity. It combines animistic beliefs with Folk Christian beliefs which had been handed by generations of diviners or healers. A descriptive qualitative method was used aided by the participant and non-participant observations. It can be deduced from the study that Spiritual folk healing practices had been robustly practiced by the healers or diviners with spiritual themes but it is also tented with the mysticism of animism. The diviner or healer is the main officiating person in the curing rituals which is usually assisted by the assistant curer or diviner.
- Published
- 2022
5. Best Participatory Practices in Mangrove Conservation Management: The Case in the Mangrove Rehabilitation Program in the Fishing Villages in the Philippines
- Author
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Tomaquin, Ramel D., primary
- Published
- 2023
- Full Text
- View/download PDF
6. HEALING PRACTICES OF THE SPIRITUAL FOLK HEALERS OF TANDAG: A CONSTRUCT OF THEIR SOCIAL REALITY AND MYSTICISM
- Author
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Ramel D. Tomaquin, PhD
- Subjects
Spiritual, Diviner, Curer, Shaman, Folk, Mananambal, Tambalon, Healer - Abstract
The paper discusses the rituals performed by the diviner or spiritual healer in curing the clients. It involves prayers, chants and elaborate ceremonies addressed to the supreme deity. It combines animistic beliefs with Folk Christian beliefs which had been handed by generations of diviners or healers. A descriptive qualitative method was used aided by the participant and non-participant observations. It can be deduced from the study that Spiritual folk healing practices had been robustly practiced by the healers or diviners with spiritual themes but it is also tented with the mysticism of animism. The diviner or healer is the main officiating person in the curing rituals which is usually assisted by the assistant curer or diviner.
- Published
- 2023
- Full Text
- View/download PDF
7. Contextualized and Localized Science Teaching and Learning Materials and Its Characteristics to Improve Students' Learning Performance
- Author
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Bello, Jayson B., Loewela S. Concon, Ma. Cindy Cristine Polache, Ayaton, Mechelle Jane C., Ramel D. Manlicayan, Jemerie P. Campomanes, and Saro, Jeffry M.
- Subjects
students ,localized ,science teaching ,learning materials ,t-test ,contextualized - Abstract
The K–12 curriculum in the Philippines emphasizes the innovative teaching and learning methodologies of localization and contextualization. Contextualization might help Filipino culture advance and encourage the next generation of educators to be more original and innovative. The purpose of the study was to determine and attest to the result of the contextualized and localized learning materials in teaching science to improve students’ learning performance among randomly selected learners in the academic year 2021–2022. The study has employed an experimental research design and followed a sampling technique in determining the participants to perform the study. The study's total sample population included 40 students. Furthermore, the assessment or examination consisted of 50 knowledge multiple-choice questions with four answers. A paired t-test for correlated means was used to determine the significant improvement between the two groups utilized in the study’s performance, and an independent t-test was used to check the significant difference between the two groups' posttest learning performances. Based on the findings, the calculated statistic t-test value was -39.722, and the p-value was 0.000 when a localized and contextualized teaching and learning process was used. And for the other group (without), it was shown that the calculated statistic value was -21.078 with a p-value of 0.000 (highly significant) for this t-test. It means that both tests were significantly better than each other because the p-value was lower than the alpha of 0.05. Therefore, when teaching and learning processes were localized and contextualized, learning performance increased considerably.
- Published
- 2023
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8. THE SOCIO-CULTURAL VIEWS OF THE MAMANWAS OF TANDAG: AN ETHNOGRAPHIC STUDY OF THE PEACE-LOVING COMMUNITY
- Author
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Ramel D. Tomaquin and Retsy Tomaquin-Malong
- Subjects
Peace, Community, Discourse, Socio-Cultural, Mamanwas, Tandag - Abstract
The following sociocultural practices or worldviews are based on a series of interviews with the Mamanwas presented in an ethnographic manner. It will discuss its birth and initiation rites, engagement and wedding customs, burial practices, indigenous value system, worldviews on natural phenomena, and indigenous values system.
- Published
- 2022
- Full Text
- View/download PDF
9. A PI3KCIIALPHA/primary cilium-dependent autophagy program protects endothelial cells in response to atheroprone shear stress
- Author
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Nasr, M., primary, Fay, A., additional, Lupieri, A., additional, Malet, N., additional, Zahreddine, R., additional, Swiader, A., additional, Wahart, A., additional, Negre-Salvayre, A., additional, Hirsch, E., additional, Monteyne, D., additional, Perez-Morga, D., additional, Dupont, N., additional, Codogno, P., additional, Ramel, D., additional, Morel, E., additional, Laffargue, M., additional, and Gayral, S., additional
- Published
- 2022
- Full Text
- View/download PDF
10. WS18.02 A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation and reduced inflammation in obstructive airway diseases
- Author
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Murabito, A., primary, Sala, V., additional, Pisano, A.R., additional, Bertolini, S., additional, Gianotti, A., additional, Caci, E., additional, Montresor, A., additional, Premchandar, A., additional, Pirozzi, F., additional, Ren, K., additional, Sala, A. Della, additional, Mergiotti, M., additional, Richter, W., additional, De Poel, E., additional, Matthey, M., additional, Caldrer, S., additional, Cardone, R.A., additional, Civiletti, F., additional, Costamagna, A., additional, Quinney, N.L., additional, Butnarasu, C., additional, Visentin, S., additional, Ruggiero, M.R., additional, Baroni, S., additional, Crich, S. Geninatti, additional, Ramel, D., additional, Laffargue, M., additional, Tocchetti, C.G., additional, Levi, R., additional, Conti, M., additional, Lu, X.-Y., additional, Melotti, P., additional, Sorio, C., additional, De Rose, V., additional, Facchinetti, F., additional, Fanelli, V., additional, Wenzel, D., additional, Fleischmann, B.K., additional, Mall, M.A., additional, Beekman, J., additional, Laudanna, C., additional, Gentzsch, M., additional, Lukacs, G.L., additional, Pedemonte, N., additional, Hirsch, E., additional, and Ghigo, A., additional
- Published
- 2022
- Full Text
- View/download PDF
11. Healing Practices of the Spiritual Folk Healers of Tandag: A Construct of their Social Reality and Mysticism
- Author
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Tomaquin, Ramel D., primary
- Published
- 2022
- Full Text
- View/download PDF
12. The Socio-Cultural Views of the Mamanwas of Tandag: An Ethnographic Study of the Peace-Loving Community
- Author
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Tomaquin, Ramel D., primary
- Published
- 2022
- Full Text
- View/download PDF
13. A murine model to study neoatherosclerosis after angioplasty: Impact of diabetes on arterial lesion
- Author
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Wahart, A., primary, Auge, N., additional, Solinhac, R., additional, Cavalerie, H., additional, Sarthou, M.-K., additional, Grzesiak, L., additional, Malet, N., additional, Salvayre, A. Negre, additional, Gayral, S., additional, Ramel, D., additional, and Laffargue, M., additional
- Published
- 2021
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14. Direct measurement of total emissivities at cryogenic temperatures: Application to satellite coatings
- Author
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Herve, P., Rambure, N., Sadou, A., Ramel, D., Francou, L., Delouard, P., and Gavila, E.
- Published
- 2008
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15. Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas
- Author
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Colomba, A, Courilleau, D, Ramel, D, Billadeau, D D, Espinos, E, Delsol, G, Payrastre, B, and Gaits-Iacovoni, F
- Published
- 2008
- Full Text
- View/download PDF
16. Noncatalytic function of PI3Kγ drives smooth muscle cell proliferation after arterial damage
- Author
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Lupieri, A., primary, Blaise, R., additional, Ghigo, A., additional, Smirnova, N., additional, Sarthou, M.-K., additional, Malet, N., additional, Limon, I., additional, Vincent, P., additional, Hirsch, E., additional, Gayral, S., additional, Ramel, D., additional, and Laffargue, M., additional
- Published
- 2020
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17. Molecular dynamics study in the Ce0.9M0.1O1.95 (M=Gd, Sm) doped and co-doped CeO2 systems: Structure and oxygen diffusion
- Author
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Vives, S., primary, Ramel, D., additional, and Meunier, C., additional
- Published
- 2019
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18. Fatigue thermique à grand nombre de cycles d'un acier inoxydable austénitique
- Author
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Ludovic Vincent, Malésys, N., Chaise, S., Perez, G., Hild, F., Philippe Le Masson, Michel Dumons, Ramel, D., Le Masson, Philippe, Laboratoire d'Ingénierie des Matériaux de Bretagne (LIMATB), Université de Bretagne Sud (UBS)-Institut Brestois du Numérique et des Mathématiques (IBNM), and Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO)
- Published
- 2007
19. R32: MMP-9 est surexprimée dans les lymphomes anaplasiques à grandes cellules NPM-ALK-positifs et activée à la surface cellulaire par la chaperonne Hsp90 pour promouvoir l’invasion
- Author
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Lagarrigue, F., primary, Dupuis-Coronas, S., additional, Ramel, D., additional, Delsol, G., additional, Tronchère, H., additional, Payrastre, B., additional, and Gaits-Iacovoni, F., additional
- Published
- 2010
- Full Text
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20. Elevated levels of PtdIns5P in NPM-ALK transformed cells: Implication of PIKfyve
- Author
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Coronas, S., primary, Lagarrigue, F., additional, Ramel, D., additional, Chicanne, G., additional, Delsol, G., additional, Payrastre, B., additional, and Tronchère, H., additional
- Published
- 2008
- Full Text
- View/download PDF
21. Activation of Rac1 and the exchange factor Vav3 are involved in NPM-ALK signaling in anaplastic large cell lymphomas
- Author
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Colomba, A, primary, Courilleau, D, additional, Ramel, D, additional, Billadeau, D D, additional, Espinos, E, additional, Delsol, G, additional, Payrastre, B, additional, and Gaits-Iacovoni, F, additional
- Published
- 2007
- Full Text
- View/download PDF
22. A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases
- Author
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Alessandra Ghigo, Alessandra Murabito, Valentina Sala, Anna Rita Pisano, Serena Bertolini, Ambra Gianotti, Emanuela Caci, Alessio Montresor, Aiswarya Premchandar, Flora Pirozzi, Kai Ren, Angela Della Sala, Marco Mergiotti, Wito Richter, Eyleen de Poel, Michaela Matthey, Sara Caldrer, Rosa A. Cardone, Federica Civiletti, Andrea Costamagna, Nancy L. Quinney, Cosmin Butnarasu, Sonja Visentin, Maria Rosaria Ruggiero, Simona Baroni, Simonetta Geninatti Crich, Damien Ramel, Muriel Laffargue, Carlo G. Tocchetti, Renzo Levi, Marco Conti, Xiao-Yun Lu, Paola Melotti, Claudio Sorio, Virginia De Rose, Fabrizio Facchinetti, Vito Fanelli, Daniela Wenzel, Bernd K. Fleischmann, Marcus A. Mall, Jeffrey Beekman, Carlo Laudanna, Martina Gentzsch, Gergely L. Lukacs, Nicoletta Pedemonte, Emilio Hirsch, Ghigo, A., Murabito, A., Sala, V., Pisano, A. R., Bertolini, S., Gianotti, A., Caci, E., Montresor, A., Premchandar, A., Pirozzi, F., Ren, K., Sala, A. D., Mergiotti, M., Richter, W., de Poel, E., Matthey, M., Caldrer, S., Cardone, R. A., Civiletti, F., Costamagna, A., Quinney, N. L., Butnarasu, C., Visentin, S., Ruggiero, M. R., Baroni, S., Crich, S. G., Ramel, D., Laffargue, M., Tocchetti, C. G., Levi, R., Conti, M., Lu, X. -Y., Melotti, P., Sorio, C., De Rose, V., Facchinetti, F., Fanelli, V., Wenzel, D., Fleischmann, B. K., Mall, M. A., Beekman, J., Laudanna, C., Gentzsch, M., Lukacs, G. L., Pedemonte, N., and Hirsch, E.
- Subjects
Inflammation ,Animal ,Cystic Fibrosis Transmembrane Conductance Regulator ,bronchus ,General Medicine ,PI3K ,Article ,lung ,Mice ,Phosphatidylinositol 3-Kinases ,CFTR, PI3K, cAMP, PKA, inflammation, lung, bronchus, airways ,cAMP ,Peptide ,Animals ,Class Ib Phosphatidylinositol 3-Kinase ,Humans ,PKA ,CFTR ,Phosphatidylinositol 3-Kinase ,airways ,Peptides ,Human - Abstract
Cyclic adenosine 3′,5′-monophosphate (cAMP)–elevating agents, such as β 2 -adrenergic receptor (β 2 -AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by β 2 -ARs in airway structural and inflammatory cells. Displacement of the PI3Kγ-anchored pool of protein kinase A (PKA) by an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited a pool of subcortical PDE4B and PDE4D and safely increased cAMP in the lungs, leading to airway smooth muscle relaxation and reduced neutrophil infiltration in a murine model of asthma. In human bronchial epithelial cells, PI3Kγ MP induced unexpected cAMP and PKA elevations restricted to the vicinity of the cystic fibrosis transmembrane conductance regulator (CFTR), the ion channel controlling mucus hydration that is mutated in cystic fibrosis (CF). PI3Kγ MP promoted the phosphorylation of wild-type CFTR on serine-737, triggering channel gating, and rescued the function of F508del-CFTR, the most prevalent CF mutant, by enhancing the effects of existing CFTR modulators. These results unveil PI3Kγ as the regulator of a β 2 -AR/cAMP microdomain central to smooth muscle contraction, immune cell activation, and epithelial fluid secretion in the airways, suggesting the use of a PI3Kγ MP for compartment-restricted, therapeutic cAMP elevation in chronic obstructive respiratory diseases.
- Published
- 2022
23. PI3KCIIα-Dependent Autophagy Program Protects From Endothelial Dysfunction and Atherosclerosis in Response to Low Shear Stress in Mice.
- Author
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Nasr M, Fay A, Lupieri A, Malet N, Darmon A, Zahreddine R, Swiader A, Wahart A, Viaud J, Nègre-Salvayre A, Hirsch E, Monteyne D, Perez-Morgà D, Dupont N, Codogno P, Ramel D, Morel E, Laffargue M, and Gayral S
- Subjects
- Animals, Humans, Mice, Apolipoproteins E genetics, Apolipoproteins E metabolism, Autophagy, Cells, Cultured, Human Umbilical Vein Endothelial Cells metabolism, Mammals, Mechanistic Target of Rapamycin Complex 1 metabolism, Stress, Mechanical, Atherosclerosis genetics, Atherosclerosis prevention & control, Atherosclerosis metabolism, Class I Phosphatidylinositol 3-Kinases metabolism
- Abstract
Background: The ability to respond to mechanical forces is a basic requirement for maintaining endothelial cell (ECs) homeostasis, which is continuously subjected to low shear stress (LSS) and high shear stress (HSS). In arteries, LSS and HSS have a differential impact on EC autophagy processes. However, it is still unclear whether LSS and HSS differently tune unique autophagic machinery or trigger specific autophagic responses in ECs., Methods: Using fluid flow system to generate forces on EC and multiscale imaging analyses on ApoE
-/- mice whole arteries, we studied the cellular and molecular mechanism involved in autophagic response to LSS or HSS on the endothelium., Results: We found that LSS and HSS trigger autophagy activation by mobilizing specific autophagic signaling modules. Indeed, LSS-induced autophagy in endothelium was independent of the class III PI3K (phosphoinositide 3-kinase) VPS34 (vacuolar sorting protein 34) but controlled by the α isoform of class II PI3K (phosphoinositide 3-kinase class II α [PI3KCIIα]). Accordingly, reduced PI3KCIIα expression in ApoE-/- mice (ApoE-/- PI3KCIIα+/- ) led to EC dysfunctions associated with increased plaque deposition in the LSS regions. Mechanistically, we revealed that PI3KCIIα inhibits mTORC1 (mammalian target of rapamycin complex 1) activation and that rapamycin treatment in ApoE-/- PI3KCIIα+/- mice specifically rescue autophagy in arterial LSS regions. Finally, we demonstrated that absence of PI3KCIIα led to decreased endothelial primary cilium biogenesis in response to LSS and that ablation of primary cilium mimics PI3KCIIα-decreased expression in EC dysfunction, suggesting that this organelle could be the mechanosensor linking PI3KCIIα and EC homeostasis., Conclusions: Our data reveal that mechanical forces variability within the arterial system determines EC autophagic response and supports a central role of PI3KCIIα/mTORC1 axis to prevent EC dysfunction in LSS regions., Competing Interests: Disclosures None.- Published
- 2024
- Full Text
- View/download PDF
24. Leucine-Rich Alpha-2 Glycoprotein 1 Accumulates in Complicated Atherosclerosis and Promotes Calcification.
- Author
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Grzesiak L, Amaya-Garrido A, Feuillet G, Malet N, Swiader A, Sarthou MK, Wahart A, Ramel D, Gayral S, Schanstra JP, Klein J, and Laffargue M
- Subjects
- Animals, Humans, Mice, Endothelial Cells metabolism, Glycoproteins genetics, Glycoproteins metabolism, Leucine metabolism, Mice, Knockout, Myocytes, Smooth Muscle metabolism, Plaque, Atherosclerotic metabolism, Atherosclerosis genetics, Atherosclerosis metabolism, Renal Insufficiency, Chronic metabolism, Vascular Calcification etiology, Vascular Calcification metabolism
- Abstract
Atherosclerosis is the primary cause of cardiovascular disease. The development of plaque complications, such as calcification and neo-angiogenesis, strongly impacts plaque stability and is a good predictor of mortality in patients with atherosclerosis. Despite well-known risk factors of plaque complications, such as diabetes mellitus and chronic kidney disease, the mechanisms involved are not fully understood. We and others have identified that the concentration of circulating leucine-rich α-2 glycoprotein 1 (LRG1) was increased in diabetic and chronic kidney disease patients. Using apolipoprotein E knockout mice (ApoE-/-) (fed with Western diet) that developed advanced atherosclerosis and using human carotid endarterectomy, we showed that LRG1 accumulated into an atherosclerotic plaque, preferentially in calcified areas. We then investigated the possible origin of LRG1 and its functions on vascular cells and found that LRG1 expression was specifically enhanced in endothelial cells via inflammatory mediators and not in vascular smooth muscle cells (VSMC). Moreover, we identified that LRG1 was able to induce calcification and SMAD1/5-signaling pathways in VSMC. In conclusion, our results identified for the first time that LRG1 is a direct contributor to vascular calcification and suggest a role of this molecule in the development of plaque complications in patients with atherosclerosis.
- Published
- 2023
- Full Text
- View/download PDF
25. Comparison of the different distribution functions in Gd-doped ceria system by molecular dynamics simulations.
- Author
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Vives S, Ramel D, and Meunier C
- Abstract
Cerium dioxide-based materials are among the most studied for applications in the energy and environmental fields and are also of interest in biology and medicine. The fluorite structure of CeO
2 is locally distorted by the concomitant presence of doping cations, such as Gd3+ and oxygen vacancies. The cation-anion bond length distribution then becomes increasingly asymmetric with the doping ratio and temperature. In these cases, the MD simulation results indicate that the commonly used maximum of the pair correlation function g ( r ) first peak can no longer be adopted to estimate the mean bond length. To determine the true cation-anion bond length, the analysis of the radial distribution function R ( r ) first peak is necessary. Furthermore, the asymmetry of this peak must be accounted for when extracting the mean value of the distribution. The gap between the g ( r ) maximum and the R ( r ) mean position derived from the fit using a skewed Gaussian function clearly increases with the doping ratio and temperature, leading to different conclusions concerning bond length evolution. The present study also suggests that care must be taken when the bond length is deduced from the pair distribution functions Gpdf ( r ) as is the case in total scattering experiments (x-ray and neutrons). Finally, relations between the cumulants of the effective distribution of distances as determined in extended x-ray absorption fine structure experiments and the cumulants describing the real distance distribution are proposed considering that both these distributions are modelled by a skewed Gaussian function., (© 2023 IOP Publishing Ltd.)- Published
- 2023
- Full Text
- View/download PDF
26. A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases.
- Author
-
Ghigo A, Murabito A, Sala V, Pisano AR, Bertolini S, Gianotti A, Caci E, Montresor A, Premchandar A, Pirozzi F, Ren K, Della Sala A, Mergiotti M, Richter W, de Poel E, Matthey M, Caldrer S, Cardone RA, Civiletti F, Costamagna A, Quinney NL, Butnarasu C, Visentin S, Ruggiero MR, Baroni S, Crich SG, Ramel D, Laffargue M, Tocchetti CG, Levi R, Conti M, Lu XY, Melotti P, Sorio C, De Rose V, Facchinetti F, Fanelli V, Wenzel D, Fleischmann BK, Mall MA, Beekman J, Laudanna C, Gentzsch M, Lukacs GL, Pedemonte N, and Hirsch E
- Subjects
- Animals, Class Ib Phosphatidylinositol 3-Kinase, Humans, Inflammation, Mice, Peptides metabolism, Phosphatidylinositol 3-Kinases metabolism, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Phosphatidylinositol 3-Kinase metabolism
- Abstract
Cyclic adenosine 3',5'-monophosphate (cAMP)-elevating agents, such as β
2 -adrenergic receptor (β2 -AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by β2 -ARs in airway structural and inflammatory cells. Displacement of the PI3Kγ-anchored pool of protein kinase A (PKA) by an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited a pool of subcortical PDE4B and PDE4D and safely increased cAMP in the lungs, leading to airway smooth muscle relaxation and reduced neutrophil infiltration in a murine model of asthma. In human bronchial epithelial cells, PI3Kγ MP induced unexpected cAMP and PKA elevations restricted to the vicinity of the cystic fibrosis transmembrane conductance regulator (CFTR), the ion channel controlling mucus hydration that is mutated in cystic fibrosis (CF). PI3Kγ MP promoted the phosphorylation of wild-type CFTR on serine-737, triggering channel gating, and rescued the function of F508del-CFTR, the most prevalent CF mutant, by enhancing the effects of existing CFTR modulators. These results unveil PI3Kγ as the regulator of a β2 -AR/cAMP microdomain central to smooth muscle contraction, immune cell activation, and epithelial fluid secretion in the airways, suggesting the use of a PI3Kγ MP for compartment-restricted, therapeutic cAMP elevation in chronic obstructive respiratory diseases.- Published
- 2022
- Full Text
- View/download PDF
27. A non-catalytic function of PI3Kγ drives smooth muscle cell proliferation after arterial damage.
- Author
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Lupieri A, Blaise R, Ghigo A, Smirnova N, Sarthou MK, Malet N, Limon I, Vincent P, Hirsch E, Gayral S, Ramel D, and Laffargue M
- Subjects
- Animals, Arteries, Cell Proliferation, Mice, Myocytes, Smooth Muscle, Phosphatidylinositol 3-Kinase, Phosphatidylinositol 3-Kinases genetics
- Abstract
Arterial remodeling in hypertension and intimal hyperplasia involves inflammation and disrupted flow, both of which contribute to smooth muscle cell dedifferentiation and proliferation. In this context, our previous results identified phosphoinositide 3-kinase γ (PI3Kγ) as an essential factor in inflammatory processes of the arterial wall. Here, we identify for the first time a kinase-independent role of nonhematopoietic PI3Kγ in the vascular wall during intimal hyperplasia using PI3Kγ-deleted mice and mice expressing a kinase-dead version of the enzyme. Moreover, we found that the absence of PI3Kγ in vascular smooth muscle cells (VSMCs) leads to modulation of cell proliferation, associated with an increase in intracellular cAMP levels. Real-time analysis of cAMP dynamics revealed that PI3Kγ modulates the degradation of cAMP in primary VSMCs independently of its kinase activity through regulation of the enzyme phosphodiesterase 4. Importantly, the use of an N-terminal competing peptide of PI3Kγ blocked primary VSMC proliferation. These data provide evidence for a kinase-independent role of PI3Kγ in arterial remodeling and reveal novel strategies targeting the docking function of PI3Kγ for the treatment of cardiovascular diseases., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
28. Protein phosphatase 1 activity controls a balance between collective and single cell modes of migration.
- Author
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Chen Y, Kotian N, Aranjuez G, Chen L, Messer CL, Burtscher A, Sawant K, Ramel D, Wang X, and McDonald JA
- Subjects
- Animals, Drosophila Proteins metabolism, Drosophila melanogaster enzymology, Drosophila melanogaster genetics, Female, Genes genetics, Genes physiology, Male, Protein Phosphatase 1 genetics, Protein Phosphatase 1 metabolism, Cell Movement physiology, Drosophila Proteins physiology, Protein Phosphatase 1 physiology
- Abstract
Collective cell migration is central to many developmental and pathological processes. However, the mechanisms that keep cell collectives together and coordinate movement of multiple cells are poorly understood. Using the Drosophila border cell migration model, we find that Protein phosphatase 1 (Pp1) activity controls collective cell cohesion and migration. Inhibition of Pp1 causes border cells to round up, dissociate, and move as single cells with altered motility. We present evidence that Pp1 promotes proper levels of cadherin-catenin complex proteins at cell-cell junctions within the cluster to keep border cells together. Pp1 further restricts actomyosin contractility to the cluster periphery rather than at individual internal border cell contacts. We show that the myosin phosphatase Pp1 complex, which inhibits non-muscle myosin-II (Myo-II) activity, coordinates border cell shape and cluster cohesion. Given the high conservation of Pp1 complexes, this study identifies Pp1 as a major regulator of collective versus single cell migration., Competing Interests: YC, NK, GA, LC, CM, AB, KS, DR, XW, JM No competing interests declared, (© 2020, Chen et al.)
- Published
- 2020
- Full Text
- View/download PDF
29. Small GTPases orchestrate cell-cell communication during collective cell movement.
- Author
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Combedazou A, Gayral S, Colombié N, Fougerat A, Laffargue M, and Ramel D
- Subjects
- Animals, Endocytosis, Humans, cdc42 GTP-Binding Protein metabolism, Cell Communication, Cell Movement, Monomeric GTP-Binding Proteins metabolism
- Abstract
Collective cell migration is a critical mechanism involved in cell movement during various physiological and pathological processes such as angiogenesis and metastasis formation. During collective movement, cells remain functionally connected and can coordinate individual cell behaviors to ensure efficient migration. A cell-cell communication process ensures this complex coordination. Although the mechanisms regulating cell-cell communication remain unclear, recent findings indicate that it is based on acto-myosin cytoskeleton tension transmission from cell to cell through adherens junctions. As for single cell migration, small GTPases of the Rho and Rab families have been shown to be critical regulators of collective motion. Here, we discuss our current understanding on how these small GTPases are themselves regulated and how they control cell-cell communication during collective migration. Moreover, we also shed light on the key role of cell-cell communication and RhoGTPases in the physiological context of endothelial cell migration during angiogenesis.
- Published
- 2020
- Full Text
- View/download PDF
30. Smooth muscle cells-derived CXCL10 prevents endothelial healing through PI3Kγ-dependent T cells response.
- Author
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Lupieri A, Smirnova NF, Solinhac R, Malet N, Benamar M, Saoudi A, Santos-Zas I, Zeboudj L, Ait-Oufella H, Hirsch E, Ohayon P, Lhermusier T, Carrié D, Arnal JF, Ramel D, Gayral S, and Laffargue M
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, Carotid Artery Injuries genetics, Carotid Artery Injuries immunology, Carotid Artery Injuries pathology, Cell Proliferation, Cells, Cultured, Class Ib Phosphatidylinositol 3-Kinase deficiency, Class Ib Phosphatidylinositol 3-Kinase genetics, Disease Models, Animal, Endothelial Cells pathology, Human Umbilical Vein Endothelial Cells metabolism, Humans, Interferon-gamma metabolism, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular immunology, Muscle, Smooth, Vascular pathology, Myocytes, Smooth Muscle immunology, Myocytes, Smooth Muscle pathology, Paracrine Communication, Re-Epithelialization, Signal Transduction, CD4-Positive T-Lymphocytes enzymology, Carotid Artery Injuries enzymology, Chemokine CXCL10 metabolism, Class Ib Phosphatidylinositol 3-Kinase metabolism, Endothelial Cells metabolism, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle metabolism, Wound Healing
- Abstract
Aims: Defects in efficient endothelial healing have been associated with complication of atherosclerosis such as post-angioplasty neoatherosclerosis and plaque erosion leading to thrombus formation. However, current preventive strategies do not consider re-endothelialization in their design. Here, we investigate mechanisms linking immune processes and defect in re-endothelialization. We especially evaluate if targeting phosphoinositide 3-kinase γ immune processes could restore endothelial healing and identify immune mediators responsible for these defects., Methods and Results: Using in vivo model of endovascular injury, we showed that both ubiquitous genetic inactivation of PI3Kγ and hematopoietic cell-specific PI3Kγ deletion improved re-endothelialization and that CD4+ T-cell population drives this effect. Accordingly, absence of PI3Kγ activity correlates with a decrease in local IFNγ secretion and its downstream interferon-inducible chemokine CXCL10. CXCL10 neutralization promoted re-endothelialization in vivo as the same level than those observed in absence of PI3Kγ suggesting a role of CXCL10 in re-endothelialization defect. Using a new established ex vivo model of carotid re-endothelialization, we showed that blocking CXCL10 restore the IFNγ-induced inhibition of endothelial healing and identify smooth muscle cells as the source of CXCL10 secretion in response to Th1 cytokine., Conclusion: Altogether, these findings expose an unforeseen cellular cross-talk within the arterial wall whereby a PI3Kγ-dependent T-cell response leads to CXCL10 production by smooth muscle cells which in turn inhibits endothelial healing. Therefore, both PI3Kγ and the IFNγ/CXCL10 axis provide novel strategies to promote endothelial healing., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
- Full Text
- View/download PDF
31. PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress.
- Author
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Boukhalfa A, Nascimbeni AC, Ramel D, Dupont N, Hirsch E, Gayral S, Laffargue M, Codogno P, and Morel E
- Subjects
- Animals, Cell Line, Cell Size, Class III Phosphatidylinositol 3-Kinases genetics, Class III Phosphatidylinositol 3-Kinases metabolism, Gene Expression Regulation, Enzymologic, Gene Knockdown Techniques, Humans, Kidney Tubules, Proximal cytology, Kidney Tubules, Proximal metabolism, Mice, Inbred C57BL, Mice, Mutant Strains, Phosphatidylinositol 3-Kinases genetics, Stress, Mechanical, Autophagy physiology, Cilia physiology, Phosphatidylinositol 3-Kinases metabolism, Phosphatidylinositol Phosphates metabolism
- Abstract
Cells subjected to stress situations mobilize specific membranes and proteins to initiate autophagy. Phosphatidylinositol-3-phosphate (PI3P), a crucial lipid in membrane dynamics, is known to be essential in this context. In addition to nutriments deprivation, autophagy is also triggered by fluid-flow induced shear stress in epithelial cells, and this specific autophagic response depends on primary cilium (PC) signaling and leads to cell size regulation. Here we report that PI3KC2α, required for ciliogenesis and PC functions, promotes the synthesis of a local pool of PI3P upon shear stress. We show that PI3KC2α depletion in cells subjected to shear stress abolishes ciliogenesis as well as the autophagy and related cell size regulation. We finally show that PI3KC2α and VPS34, the two main enzymes responsible for PI3P synthesis, have different roles during autophagy, depending on the type of cellular stress: while VPS34 is clearly required for starvation-induced autophagy, PI3KC2α participates only in shear stress-dependent autophagy.
- Published
- 2020
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- View/download PDF
32. Immune and Smooth Muscle Cells Interactions in Atherosclerosis: How to Target a Breaking Bad Dialogue?
- Author
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Ramel D, Gayral S, Sarthou MK, Augé N, Nègre-Salvayre A, and Laffargue M
- Abstract
Inflammation is a well-known pathophysiological factor of atherosclerosis but its therapeutic targeting has long been ignored. However, recent advances in the understanding of the immune mechanisms implicated in atherosclerosis have unveiled several therapeutic targets currently undergoing clinical trials. These studies have also shed light on a dialogue between the immune compartment and vascular smooth muscle cells (VSMCs) that plays a critical role in atherosclerotic disease initiation, progression, and stabilization. Our review focuses on the link between cellular and soluble immune effectors and VSMC behavior at different phases of the pathology. Furthermore, we discuss the potential targeting of these interactions to efficiently prevent cardiovascular diseases., (Copyright © 2019 Ramel, Gayral, Sarthou, Augé, Nègre-Salvayre and Laffargue.)
- Published
- 2019
- Full Text
- View/download PDF
33. Non-autonomous role of Cdc42 in cell-cell communication during collective migration.
- Author
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Colombié N, Choesmel-Cadamuro V, Series J, Emery G, Wang X, and Ramel D
- Subjects
- Animals, Cell Surface Extensions metabolism, Endocytosis, Models, Biological, Cell Communication, Cell Movement, Drosophila Proteins metabolism, Drosophila melanogaster cytology, Drosophila melanogaster metabolism, GTP-Binding Proteins metabolism
- Abstract
Collective cell migration is involved in numerous processes both physiological, such as embryonic development, and pathological such as metastasis. Compared to single cell migration, collective motion requires cell behaviour coordination through an as-yet poorly understood but critical cell-cell communication mechanism. Using Drosophila border cell migration, we show here that the small Rho GTPase Cdc42 regulates cell-cell communication. Indeed, we demonstrate that Cdc42 controls protrusion formation in a cell non-autonomous manner. Moreover, we found that the endocytic small GTPase Rab11, controls Cdc42 localisation to the periphery of migrating border cell clusters. Accordingly, over-expression of Cdc42 in border cells rescues the loss of Rab11 function. In addition, we showed that Cdc42 acts upstream of Moesin, a cytoskeletal regulator known to function downstream of rab11. Thus, our study positions Cdc42 as a new key player in cell-cell communication, acting downstream of Rab11., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
34. Myosin II governs collective cell migration behaviour downstream of guidance receptor signalling.
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Combedazou A, Choesmel-Cadamuro V, Gay G, Liu J, Dupré L, Ramel D, and Wang X
- Subjects
- Animals, ErbB Receptors metabolism, Rotation, Time-Lapse Imaging, Cell Movement, Drosophila Proteins metabolism, Drosophila melanogaster cytology, Drosophila melanogaster metabolism, Myosin Type II metabolism, Receptor Protein-Tyrosine Kinases metabolism, Signal Transduction
- Abstract
Border cell migration during Drosophila oogenesis is a potent model to study collective cell migration, a process involved in development and metastasis. Border cell clusters adopt two main types of behaviour during migration: linear and rotational. However, the molecular mechanism controlling the switch from one to the other is unknown. Here, we demonstrate that non-muscle Myosin II (NMII, also known as Spaghetti squash) activity controls the linear-to-rotational switch. Furthermore, we show that the regulation of NMII takes place downstream of guidance receptor signalling and is critical to ensure efficient collective migration. This study thus provides new insight into the molecular mechanism coordinating the different cell behaviours in a migrating cluster., (© 2017. Published by The Company of Biologists Ltd.)
- Published
- 2017
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35. Phosphatidylinositol 5-phosphate regulates invasion through binding and activation of Tiam1.
- Author
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Viaud J, Lagarrigue F, Ramel D, Allart S, Chicanne G, Ceccato L, Courilleau D, Xuereb JM, Pertz O, Payrastre B, and Gaits-Iacovoni F
- Subjects
- Actins metabolism, Bacterial Proteins metabolism, Fibroblast Growth Factor 1 pharmacology, Humans, Lymphoma, Large-Cell, Anaplastic metabolism, Neoplasm Invasiveness, Phosphoric Monoester Hydrolases metabolism, Shigella flexneri pathogenicity, T-Lymphoma Invasion and Metastasis-inducing Protein 1, Guanine Nucleotide Exchange Factors metabolism, Lymphoma, Large-Cell, Anaplastic pathology, Phosphatidylinositol Phosphates metabolism, cdc42 GTP-Binding Protein metabolism, rac1 GTP-Binding Protein metabolism
- Abstract
PtdIns5P is a lipid messenger acting as a stress-response mediator in the nucleus, and known to maintain cell activation through traffic alterations upon bacterial infection. Here, we show that PtdIns5P regulates actin dynamics and invasion via recruitment and activation of the exchange factor Tiam1 and Rac1. Restricted Rac1 activation results from the binding of Tiam1 DH-PH domains to PtdIns5P. Using an assay that mimics Rac1 membrane anchoring by using Rac1-His and liposomes containing Ni(2+)-NTA modified lipids, we demonstrate that intrinsic Tiam1 DH-PH activity increases when Rac1 is anchored in a PtdIns5P-enriched environment. This pathway appears to be general since it is valid in different pathophysiological models: receptor tyrosine kinase activation, bacterial phosphatase IpgD expression and the invasive NPM-ALK(+) lymphomas. The discovery that PtdIns5P could be a keystone of GTPases and cytoskeleton spatiotemporal regulation opens important research avenues towards unravelling new strategies counteracting cell invasion.
- Published
- 2014
- Full Text
- View/download PDF
36. Cell coordination of collective migration by Rab11 and Moesin.
- Author
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Emery G and Ramel D
- Abstract
Cell migration is an important process involved in developmental events and in pathologies such as cancer. Cell migration can be classified into two types: individual and collective cell movements. Compared with individual migration, collective cell migration is less understood and has drawn increasing attention lately because of its emerging role in cancer spreading. We have recently established that Rab11 is absolutely required for spatial control of Rac1 activity through the control of cell-cell communication during collective movements (Ramel, et al. 2013). Moreover, we demonstrated that Rab11 acts through the control of Moesin activity. Here, we discuss how Rab11 and Moesin could cooperate to transfer forces from cell to cell in order to insure coordinated collective cell migration.
- Published
- 2013
- Full Text
- View/download PDF
37. GTP exchange factor Vav regulates guided cell migration by coupling guidance receptor signalling to local Rac activation.
- Author
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Fernández-Espartero CH, Ramel D, Farago M, Malartre M, Luque CM, Limanovich S, Katzav S, Emery G, and Martín-Bermudo MD
- Subjects
- Animals, Animals, Genetically Modified, Cell Movement genetics, Cell Surface Extensions genetics, Cells, Cultured, Drosophila melanogaster cytology, Embryo, Nonmammalian cytology, Embryo, Nonmammalian metabolism, Enzyme Repression genetics, Female, Morphogenesis genetics, Proto-Oncogene Proteins c-vav genetics, RNA, Small Interfering genetics, Sequence Deletion genetics, Two-Hybrid System Techniques, Drosophila melanogaster physiology, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-vav metabolism
- Abstract
Guided cell migration is a key mechanism for cell positioning in morphogenesis. The current model suggests that the spatially controlled activation of receptor tyrosine kinases (RTKs) by guidance cues limits Rac activity at the leading edge, which is crucial for establishing and maintaining polarized cell protrusions at the front. However, little is known about the mechanisms by which RTKs control the local activation of Rac. Here, using a multidisciplinary approach, we identify the GTP exchange factor (GEF) Vav as a key regulator of Rac activity downstream of RTKs in a developmentally regulated cell migration event, that of the Drosophila border cells (BCs). We show that elimination of the vav gene impairs BC migration. Live imaging analysis reveals that vav is required for the stabilization and maintenance of protrusions at the front of the BC cluster. In addition, activation of the PDGF/VEGF-related receptor (PVR) by its ligand the PDGF/PVF1 factor brings about activation of Vav protein by direct interaction with the intracellular domain of PVR. Finally, FRET analyses demonstrate that Vav is required in BCs for the asymmetric distribution of Rac activity at the front. Our results unravel an important role for the Vav proteins as signal transducers that couple signalling downstream of RTKs with local Rac activation during morphogenetic movements.
- Published
- 2013
- Full Text
- View/download PDF
38. Rab11 regulates cell-cell communication during collective cell movements.
- Author
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Ramel D, Wang X, Laflamme C, Montell DJ, and Emery G
- Subjects
- Actin Cytoskeleton, Animals, Drosophila Proteins genetics, Drosophila melanogaster metabolism, Flow Cytometry, Fluorescence Resonance Energy Transfer, Immunoprecipitation, Membrane Proteins genetics, RNA, Small Interfering genetics, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, rab GTP-Binding Proteins genetics, rab5 GTP-Binding Proteins genetics, rac GTP-Binding Proteins genetics, Cell Communication, Cell Movement physiology, Drosophila Proteins metabolism, Drosophila melanogaster genetics, Membrane Proteins metabolism, rab GTP-Binding Proteins metabolism, rab5 GTP-Binding Proteins metabolism, rac GTP-Binding Proteins metabolism
- Abstract
Collective cell movements contribute to development and metastasis. The small GTPase Rac is a key regulator of actin dynamics and cell migration but the mechanisms that restrict Rac activation and localization in a group of collectively migrating cells are unknown. Here, we demonstrate that the small GTPases Rab5 and Rab11 regulate Rac activity and polarization during collective cell migration. We use photoactivatable forms of Rac to demonstrate that Rab11 acts on the entire group to ensure that Rac activity is properly restricted to the leading cell through regulation of cell-cell communication. In addition, we show that Rab11 binds to the actin cytoskeleton regulator Moesin and regulates its activation in vivo during migration. Accordingly, reducing the level of Moesin activity also affects cell-cell communication, whereas expressing active Moesin rescues loss of Rab11 function. Our model suggests that Rab11 controls the sensing of the relative levels of Rac activity in a group of cells, leading to the organization of individual cells in a coherent multicellular motile structure.
- Published
- 2013
- Full Text
- View/download PDF
39. Evi5 promotes collective cell migration through its Rab-GAP activity.
- Author
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Laflamme C, Assaker G, Ramel D, Dorn JF, She D, Maddox PS, and Emery G
- Subjects
- Animals, Drosophila Proteins genetics, Drosophila melanogaster genetics, Female, GTPase-Activating Proteins genetics, Intracellular Signaling Peptides and Proteins genetics, Ovary metabolism, Cell Movement physiology, Drosophila Proteins metabolism, Drosophila melanogaster metabolism, GTPase-Activating Proteins metabolism, Intracellular Signaling Peptides and Proteins metabolism, rab GTP-Binding Proteins metabolism
- Abstract
Membrane trafficking has well-defined roles during cell migration. However, its regulation is poorly characterized. In this paper, we describe the first screen for putative Rab-GTPase-activating proteins (GAPs) during collective cell migration of Drosophila melanogaster border cells (BCs), identify the uncharacterized Drosophila protein Evi5 as an essential membrane trafficking regulator, and describe the molecular mechanism by which Evi5 regulates BC migration. Evi5 requires its Rab-GAP activity to fulfill its functions during migration and acts as a GAP protein for Rab11. Both loss and gain of Evi5 function blocked BC migration by disrupting the Rab11-dependent polarization of active guidance receptors. Altogether, our findings deepen our understanding of the molecular machinery regulating endocytosis and subsequently cell signaling during migration.
- Published
- 2012
- Full Text
- View/download PDF
40. Shigella flexneri infection generates the lipid PI5P to alter endocytosis and prevent termination of EGFR signaling.
- Author
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Ramel D, Lagarrigue F, Pons V, Mounier J, Dupuis-Coronas S, Chicanne G, Sansonetti PJ, Gaits-Iacovoni F, Tronchère H, and Payrastre B
- Subjects
- Bacterial Proteins biosynthesis, Bacterial Proteins genetics, Cell Survival, Dysentery, Bacillary genetics, Endosomes genetics, Endosomes metabolism, Endosomes microbiology, Enzyme Activation genetics, ErbB Receptors genetics, HeLa Cells, Humans, Lysosomes genetics, Lysosomes metabolism, Lysosomes microbiology, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Phosphatidylinositol Phosphates genetics, Phosphoric Monoester Hydrolases biosynthesis, Phosphoric Monoester Hydrolases genetics, Protein Transport genetics, Proteolysis, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, Shigella flexneri genetics, Dysentery, Bacillary enzymology, Endocytosis, ErbB Receptors metabolism, Phosphatidylinositol Phosphates metabolism, Shigella flexneri enzymology, Signal Transduction
- Abstract
The phosphoinositide metabolic pathway, which regulates cellular processes implicated in survival, motility, and trafficking, is often subverted by bacterial pathogens. Shigella flexneri, a bacterium that causes dysentery, injects IpgD, a phosphoinositide phosphatase that generates the lipid phosphatidylinositol 5-phosphate (PI5P), into host cells, thereby activating the phosphoinositide 3-kinase-Akt survival pathway. We show that epidermal growth factor receptor (EGFR) is required for PI5P-dependent activation of Akt in infected HeLa cells or cells ectopically expressing IpgD. Cells treated with PI5P had increased numbers of early endosomes with activated EGFR, no detectable EGFR in the late endosomal or lysosomal compartments, and prolonged EGFR signaling. Endosomal recycling and retrograde pathways were spared, indicating that the effect of PI5P on the degradative route to the late endocytic compartments was specific. Thus, we identified PI5P, which was enriched in endosomes, as a regulator of vesicular trafficking that alters growth factor receptor signaling by impairing lysosomal degradation, a property used by S. flexneri to favor survival of host cells.
- Published
- 2011
- Full Text
- View/download PDF
41. The nucleophosmin-anaplastic lymphoma kinase oncogene interacts, activates, and uses the kinase PIKfyve to increase invasiveness.
- Author
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Dupuis-Coronas S, Lagarrigue F, Ramel D, Chicanne G, Saland E, Gaits-Iacovoni F, Payrastre B, and Tronchère H
- Subjects
- Animals, Cell Line, Tumor, Cell Movement, Gene Silencing, Humans, Matrix Metalloproteinase 9 genetics, Matrix Metalloproteinase 9 metabolism, Mice, NIH 3T3 Cells, Neoplasm Invasiveness, Oncogene Proteins, Fusion genetics, Phosphatidylinositol 3-Kinases genetics, Protein-Tyrosine Kinases genetics, Cell Proliferation, Oncogene Proteins, Fusion metabolism, Phosphatidylinositol 3-Kinases metabolism, Protein-Tyrosine Kinases metabolism
- Abstract
NPM-ALK is a chimeric tyrosine kinase detected in most anaplastic large cell lymphomas that results from the reciprocal translocation t(2,5)(p23;q35) that fuses the N-terminal domain of nucleophosmin (NPM) to the catalytic domain of the anaplastic lymphoma kinase (ALK) receptor. The constitutive activity of the kinase is responsible for its oncogenicity through the stimulation of several downstream signaling pathways, leading to cell proliferation, migration, and survival. We demonstrated previously that the high level of phosphatidylinositol 5-phosphate measured in NPM-ALK-expressing cells is controlled by the phosphoinositide kinase PIKfyve, a lipid kinase known for its role in vesicular trafficking. Here, we show that PIKfyve associates with NPM-ALK and that the interaction involves the 181-300 region of the oncogene. Moreover, we demonstrate that the tyrosine kinase activity of the oncogene controls PIKfyve lipid kinase activity but is dispensable for the formation of the complex. Silencing or inhibition of PIKfyve using siRNA or the PIKfyve inhibitor YM201636 have no effect on NPM-ALK-mediated proliferation and migration but strongly reduce invasive capacities of NPM-ALK-expressing cells and their capacity to degrade the extracellular matrix. Accordingly, immunofluorescence studies confirm a perturbation of matrix metalloproteinase 9 localization at the cell surface and defect in maturation. Altogether, these results suggest a role for PIKfyve in NPM-ALK-mediated invasion.
- Published
- 2011
- Full Text
- View/download PDF
42. Spatial restriction of receptor tyrosine kinase activity through a polarized endocytic cycle controls border cell migration.
- Author
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Assaker G, Ramel D, Wculek SK, González-Gaitán M, and Emery G
- Subjects
- Animals, Cell Polarity, Drosophila Proteins genetics, Drosophila Proteins metabolism, Drosophila melanogaster cytology, Drosophila melanogaster genetics, Drosophila melanogaster metabolism, Endosomes metabolism, ErbB Receptors metabolism, Female, Luminescent Proteins genetics, Luminescent Proteins metabolism, Microscopy, Confocal, Oocytes cytology, RNA Interference, Receptors, Invertebrate Peptide metabolism, Time Factors, Vesicular Transport Proteins genetics, Vesicular Transport Proteins metabolism, rab GTP-Binding Proteins genetics, rab GTP-Binding Proteins metabolism, rab4 GTP-Binding Proteins genetics, rab4 GTP-Binding Proteins metabolism, rab7 GTP-Binding Proteins, Cell Movement physiology, Endocytosis physiology, Oocytes metabolism, Receptor Protein-Tyrosine Kinases metabolism
- Abstract
Border cell migration is a stereotyped migration occurring during the development of the Drosophila egg chamber. During this process, a cluster composed of six to eight follicle cells migrates between nurse cells toward the oocyte. Receptor tyrosine kinases (RTKs) are enriched at the leading edge of the follicle cells and establish the directionality of their migration. Endocytosis has been shown to play a role in the maintenance of this polarization; however, the mechanisms involved are largely unknown. In this study, we show that border cell migration requires the function of the small GTPases Rab5 and Rab11 that regulate trafficking through the early and the recycling endosome, respectively. Expression of a dominant negative form of rab11 induces a loss of the polarization of RTK activity, which correlates with a severe migration phenotype. In addition, we demonstrate that the exocyst component Sec15 is distributed in structures that are polarized during the migration process in a Rab11-dependent manner and that the down-regulation of different subunits of the exocyst also affects migration. Together, our data demonstrate a fundamental role for a plasma membrane-endosome trafficking cycle in the maintenance of active RTK at the leading edge of border cells during their migration.
- Published
- 2010
- Full Text
- View/download PDF
43. Matrix metalloproteinase-9 is upregulated in nucleophosmin-anaplastic lymphoma kinase-positive anaplastic lymphomas and activated at the cell surface by the chaperone heat shock protein 90 to promote cell invasion.
- Author
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Lagarrigue F, Dupuis-Coronas S, Ramel D, Delsol G, Tronchère H, Payrastre B, and Gaits-Iacovoni F
- Subjects
- Cell Line, Tumor, Cell Membrane metabolism, Dipeptides pharmacology, Enzyme Activation, Enzyme Precursors metabolism, Humans, Hyaluronan Receptors metabolism, Lymphoma, Large-Cell, Anaplastic genetics, Lymphoma, Large-Cell, Anaplastic pathology, Matrix Metalloproteinase 9 genetics, Matrix Metalloproteinase 9 metabolism, Matrix Metalloproteinase Inhibitors, Neoplasm Invasiveness, Protein-Tyrosine Kinases genetics, Up-Regulation, rac1 GTP-Binding Protein metabolism, HSP90 Heat-Shock Proteins metabolism, Lymphoma, Large-Cell, Anaplastic metabolism, Matrix Metalloproteinase 9 biosynthesis, Protein-Tyrosine Kinases biosynthesis
- Abstract
Many anaplastic large cell lymphomas (ALCL) express the chimeric oncogene NPM-ALK, which drives malignant transformation and invasion. In this study, we show that NPM-ALK expression increases matrix metalloproteinase-9 (MMP-9) expression. Accordingly, we found that 100% of a large panel of ALK(+) ALCL biopsies examined were also MMP-9(+), in contrast to only 36.3% of ALK(-) tumors. Mechanistic studies revealed that Rac1 drove MMP-9 secretion. The MMP inhibitor GM6001 and MMP-9 blocking antibodies abolished the invasiveness of NPM-ALK(+) cells. Interestingly, the hyaluronan receptor CD44 acted as a docking surface for MMP-9 and the chaperone heat shock protein 90 on the cell surface, where MMP-9 was cleaved and activated. Membrane-associated MMP-9 was localized to invadopodia, which display a strong gelatinase activity. Taken together, our observations strengthen the concept that chaperones have a major extracellular role in the regulation of protein activation status, and reveal new factors that are crucial for spreading and invasion of ALK(+) ALCL. They also point out new factors crucial for ALK(+) ALCL.
- Published
- 2010
- Full Text
- View/download PDF
44. PtdIns5P protects Akt from dephosphorylation through PP2A inhibition.
- Author
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Ramel D, Lagarrigue F, Dupuis-Coronas S, Chicanne G, Leslie N, Gaits-Iacovoni F, Payrastre B, and Tronchère H
- Subjects
- HeLa Cells, Humans, PTEN Phosphohydrolase antagonists & inhibitors, Phosphatidylinositol Phosphates pharmacology, Phosphorylation, Protein Phosphatase 2 antagonists & inhibitors, Shigella flexneri metabolism, PTEN Phosphohydrolase metabolism, Phosphatidylinositol Phosphates metabolism, Protein Phosphatase 2 metabolism, Proto-Oncogene Proteins c-akt metabolism
- Abstract
Phosphatidylinositol 5-phosphate (PtdIns5P), the most recently discovered phosphoinositide, has been proposed to play a role as a lipid mediator of intracellular signaling. We have previously shown that PtdIns5P generated by IpgD, an effector of the causative agent of dysentery Shigella flexneri, activates the PI 3-kinase/Akt pathway. Here, we demonstrate that PtdIns5P is able to protect Akt from dephosphorylation. This effect is not due to inhibition of the phosphoinositide phosphatase regulating PtdIns(3,4,5)P(3) levels PTEN but rather to PtdIns5P-induced phosphorylation and subsequent inhibition of the catalytic subunit of PP2A phosphatases. These data shed light on a new mechanism used by S. flexneri bacteria to sustain Akt activation to increase survival of the host cells during bacterial replication.
- Published
- 2009
- Full Text
- View/download PDF
45. PtdIns5P: a little phosphoinositide with big functions?
- Author
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Coronas S, Ramel D, Pendaries C, Gaits-Iacovoni F, Tronchère H, and Payrastre B
- Subjects
- Humans, Models, Biological, Phosphatidylinositol Phosphates physiology
- Abstract
Phosphoinositides are minor constituents of cell membranes playing a critical role in the regulation of many cellular functions. Recent discoveries indicate that mutations in several phosphoinositide kinases and phosphatases generate imbalances in the levels of phosphoinositides, thereby leading to the development of human diseases. Although the roles of phosphoinositide 3-kinase products and PtdIns(4,5)P2 were largely studied these last years, the potential role of phosphatidylinositol monophosphates as direct signalling molecules is just emerging. PtdIns5P, the least characterized phosphoinositide, appears to be a new player in cell regulation. This review will summarize the current knowledge on the mechanisms of synthesis and degradation of PtdIns5P as well as its potential roles.
- Published
- 2007
- Full Text
- View/download PDF
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