Tau Phosphorylation by GSK3 in Different Conditions

Almost a 20% of the residues of tau protein are phosphorylatable amino acids: serine, threonine, and tyrosine. In this paper we comment on the consequences for tau of being a phosphoprotein. We will focus on serine/threonine phosphorylation. It will be discussed that, depending on the modified residue in tau molecule, phosphorylation could be protective, in processes like hibernation, or toxic like in development of those diseases known as tauopathies, which are characterized by an hyperphosphorylation and aggregation of tau

Biohybrids of scaffolding hyaluronic acid biomaterials plus adipose stem cells home local neural stem and endothelial cells: Implications for reconstruction of brain lesions after stroke.

[EN] Endogenous neurogenesis in stroke is insufficient to replace the lost brain tissue, largely due to the lack of a proper biological structure to let new cells dwell in the damaged area. We hypothesized that scaffolds made of hyaluronic acid (HA) biomaterials (BM) could provide a suitable environment to home not only new neurons, but also vessels, glia and neurofilaments. Further, the addition of exogenous cells, such as adipose stem cells (ASC) could increase this effect. Athymic mice were randomly assigned to a one of four group: stroke alone, stroke and implantation of BM, stroke and implantation of BM with ASC, and sham operated animals. Stroke model consisted of middle cerebral artery thrombosis with FeCl3. After 30 days, animals underwent magnetic resonance imaging (MRI) and were sacrificed. Proliferation and neurogenesis increased at the subventricular zone ipsilateral to the ventricle and neuroblasts, glial, and endothelial cells forming capillaries were seen inside the BM. Those effects increased when ASC were added, while there was less inflammatory reaction. Three-dimensional scaffolds made of HA are able to home newly formed neurons, glia, and endothelial cells permitting the growth neurofilaments inside them. The addition of ASC increase these effects and decrease the inflammatory reaction to the implant.Contract grant sponsor: CIBER BBN Contract grant sponsor: ERANET NEURON CALL; contract grant number: PRI-PIMNEU-2011-1372 Contract grant sponsor: Spanish Science & Innovation Ministery; contract grant number: MAT 2011-28791-C03-01, MAT 2011-28791-C03-02 an Contract grant sponsor: TERCEL; contract grant number: RD12/0019/0010 Contract grant sponsor: Spanish Ministry of Economy and Competitiveness through grants MAT2015-66666-C3, and DPI2015-72863-EXPSanchez-Rojas, L.; Gómez-Pinedo, U.; Benito-Martin, MS.; León-Espinosa, G.; Rascón-Ramirez, F.; Lendinez, C.; Martínez-Ramos, C.... (2019). Biohybrids of scaffolding hyaluronic acid biomaterials plus adipose stem cells home local neural stem and endothelial cells: Implications for reconstruction of brain lesions after stroke. Journal of Biomedical Materials Research Part B Applied Biomaterials. 107(5):1598-1606. https://doi.org/10.1002/jbm.b.34252S159816061075Azad, T. D., Veeravagu, A., & Steinberg, G. K. (2016). Neurorestoration after stroke. Neurosurgical Focus, 40(5), E2. doi:10.3171/2016.2.focus15637Faralli, A., Bigoni, M., Mauro, A., Rossi, F., & Carulli, D. (2013). Noninvasive Strategies to Promote Functional Recovery after Stroke. Neural Plasticity, 2013, 1-16. doi:10.1155/2013/854597Yamashita, T., Ninomiya, M., Hernandez Acosta, P., Garcia-Verdugo, J. M., Sunabori, T., Sakaguchi, M., … Sawamoto, K. (2006). Subventricular Zone-Derived Neuroblasts Migrate and Differentiate into Mature Neurons in the Post-Stroke Adult Striatum. Journal of Neuroscience, 26(24), 6627-6636. doi:10.1523/jneurosci.0149-06.2006Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z., & Lindvall, O. (2002). Neuronal replacement from endogenous precursors in the adult brain after stroke. Nature Medicine, 8(9), 963-970. doi:10.1038/nm747Doeppner, T. R., & Hermann, D. M. (2015). Editorial: Stem cells and progenitor cells in ischemic stroke—fashion or future? Frontiers in Cellular Neuroscience, 9. doi:10.3389/fncel.2015.00334Zhang, Z. G., & Chopp, M. (2015). Promoting brain remodeling to aid in stroke recovery. Trends in Molecular Medicine, 21(9), 543-548. doi:10.1016/j.molmed.2015.07.005Crapo, P. M., Medberry, C. J., Reing, J. E., Tottey, S., van der Merwe, Y., Jones, K. E., & Badylak, S. F. (2012). Biologic scaffolds composed of central nervous system extracellular matrix. Biomaterials, 33(13), 3539-3547. doi:10.1016/j.biomaterials.2012.01.044Ju, R., Wen, Y., Gou, R., Wang, Y., & Xu, Q. (2014). The Experimental Therapy on Brain Ischemia by Improvement of Local Angiogenesis with Tissue Engineering in the Mouse. Cell Transplantation, 23(1_suppl), 83-95. doi:10.3727/096368914x684998Zhou, K., Motamed, S., Thouas, G. A., Bernard, C. C., Li, D., Parkington, H. C., … Forsythe, J. S. (2016). Graphene Functionalized Scaffolds Reduce the Inflammatory Response and Supports Endogenous Neuroblast Migration when Implanted in the Adult Brain. PLOS ONE, 11(3), e0151589. doi:10.1371/journal.pone.0151589Elias, P. Z., & Spector, M. (2012). Implantation of a collagen scaffold seeded with adult rat hippocampal progenitors in a rat model of penetrating brain injury. Journal of Neuroscience Methods, 209(1), 199-211. doi:10.1016/j.jneumeth.2012.06.003Tang, J. D., & Lampe, K. J. (2018). From de novo peptides to native proteins: advancements in biomaterial scaffolds for acute ischemic stroke repair. Biomedical Materials, 13(3), 034103. doi:10.1088/1748-605x/aaa4c3Nih, L. R., Carmichael, S. T., & Segura, T. (2016). Hydrogels for brain repair after stroke: an emerging treatment option. Current Opinion in Biotechnology, 40, 155-163. doi:10.1016/j.copbio.2016.04.021Moshayedi, P., Nih, L. R., Llorente, I. L., Berg, A. R., Cinkornpumin, J., Lowry, W. E., … Carmichael, S. T. (2016). Systematic optimization of an engineered hydrogel allows for selective control of human neural stem cell survival and differentiation after transplantation in the stroke brain. Biomaterials, 105, 145-155. doi:10.1016/j.biomaterials.2016.07.028Lindvall, O., & Kokaia, Z. (2011). Stem Cell Research in Stroke. Stroke, 42(8), 2369-2375. doi:10.1161/strokeaha.110.599654Reis, C., Wilkinson, M., Reis, H., Akyol, O., Gospodarev, V., Araujo, C., … Zhang, J. H. (2017). A Look into Stem Cell Therapy: Exploring the Options for Treatment of Ischemic Stroke. Stem Cells International, 2017, 1-14. doi:10.1155/2017/3267352Ikegame, Y., Yamashita, K., Hayashi, S.-I., Mizuno, H., Tawada, M., You, F., … Iwama, T. (2011). Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy. Cytotherapy, 13(6), 675-685. doi:10.3109/14653249.2010.549122Wei, X., Zhao, L., Zhong, J., Gu, H., Feng, D., Johnstone, B. H., … Du, Y. (2009). Adipose stromal cells-secreted neuroprotective media against neuronal apoptosis. Neuroscience Letters, 462(1), 76-79. doi:10.1016/j.neulet.2009.06.054Gómez-Pinedo, U., Sanchez-Rojas, L., Benito-Martin, M. S., Lendinez, C., León-Espinosa, G., Rascón-Ramirez, F. J., … Barcia, J. A. (2018). Evaluation of the Safety and Efficacy of the Therapeutic Potential of Adipose-Derived Stem Cells Injected in the Cerebral Ischemic Penumbra. Journal of Stroke and Cerebrovascular Diseases, 27(9), 2453-2465. doi:10.1016/j.jstrokecerebrovasdis.2018.05.001Rodríguez-Pérez, E., Lloret Compañ, A., Monleón Pradas, M., & Martínez-Ramos, C. (2016). Scaffolds of Hyaluronic Acid-Poly(Ethyl Acrylate) Interpenetrating Networks: Characterization and In Vitro Studies. Macromolecular Bioscience, 16(8), 1147-1157. doi:10.1002/mabi.201600028Davoust, C., Plas, B., Béduer, A., Demain, B., Salabert, A.-S., Sol, J. C., … Loubinoux, I. (2017). Regenerative potential of primary adult human neural stem cells on micropatterned bio-implants boosts motor recovery. Stem Cell Research & Therapy, 8(1). doi:10.1186/s13287-017-0702-3Bateman, M. E., Strong, A. L., Gimble, J. M., & Bunnell, B. A. (2018). Concise Review: Using Fat to Fight Disease: A Systematic Review of Nonhomologous Adipose-Derived Stromal/Stem Cell Therapies. STEM CELLS, 36(9), 1311-1328. doi:10.1002/stem.2847Seo, J. H., Kim, H., Park, E. S., Lee, J. E., Kim, D. W., Kim, H. O., … Cho, S.-R. (2013). Environmental Enrichment Synergistically Improves Functional Recovery by Transplanted Adipose Stem Cells in Chronic Hypoxic-Ischemic Brain Injury. Cell Transplantation, 22(9), 1553-1568. doi:10.3727/096368912x662390Palma-Tortosa, S., García-Culebras, A., Moraga, A., Hurtado, O., Perez-Ruiz, A., Durán-Laforet, V., … Lizasoain, I. (2017). Specific Features of SVZ Neurogenesis After Cortical Ischemia: a Longitudinal Study. Scientific Reports, 7(1). doi:10.1038/s41598-017-16109-7Lu, J., Manaenko, A., & Hu, Q. (2017). Targeting Adult Neurogenesis for Poststroke Therapy. Stem Cells International, 2017, 1-10. doi:10.1155/2017/5868632Faiz, M., Sachewsky, N., Gascón, S., Bang, K. W. A., Morshead, C. M., & Nagy, A. (2015). Adult Neural Stem Cells from the Subventricular Zone Give Rise to Reactive Astrocytes in the Cortex after Stroke. Cell Stem Cell, 17(5), 624-634. doi:10.1016/j.stem.2015.08.002Moraga, A., Pradillo, J. M., García-Culebras, A., Palma-Tortosa, S., Ballesteros, I., Hernández-Jiménez, M., … Lizasoain, I. (2015). Aging increases microglial proliferation, delays cell migration, and decreases cortical neurogenesis after focal cerebral ischemia. Journal of Neuroinflammation, 12(1). doi:10.1186/s12974-015-0314-8Oh, J. S., Park, I. S., Kim, K. N., Yoon, D. H., Kim, S.-H., & Ha, Y. (2012). Transplantation of an adipose stem cell cluster in a spinal cord injury. NeuroReport, 23(5), 277-282. doi:10.1097/wnr.0b013e3283505ae2Erba, P., Terenghi, G., & J. Kingham, P. (2010). Neural Differentiation and Therapeutic Potential of Adipose Tissue Derived Stem Cells. Current Stem Cell Research & Therapy, 5(2), 153-160. doi:10.2174/157488810791268645Grudzenski, S., Baier, S., Ebert, A., Pullens, P., Lemke, A., Bieback, K., … Fatar, M. (2017). The effect of adipose tissue-derived stem cells in a middle cerebral artery occlusion stroke model depends on their engraftment rate. Stem Cell Research & Therapy, 8(1). doi:10.1186/s13287-017-0545-yEgashira, Y., Sugitani, S., Suzuki, Y., Mishiro, K., Tsuruma, K., Shimazawa, M., … Hara, H. (2012). The conditioned medium of murine and human adipose-derived stem cells exerts neuroprotective effects against experimental stroke model. Brain Research, 1461, 87-95. doi:10.1016/j.brainres.2012.04.033Cunningham, C. J., Redondo-Castro, E., & Allan, S. M. (2018). The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. Journal of Cerebral Blood Flow & Metabolism, 38(8), 1276-1292. doi:10.1177/0271678x18776802Gutiérrez-Fernández, M., Otero-Ortega, L., Ramos-Cejudo, J., Rodríguez-Frutos, B., Fuentes, B., & Díez-Tejedor, E. (2015). Adipose tissue-derived mesenchymal stem cells as a strategy to improve recovery after stroke. Expert Opinion on Biological Therapy, 15(6), 873-881. doi:10.1517/14712598.2015.1040386Pérez‐GarnesM BarciaJA Gómez‐PinedoU Monleón PradasM Vallés‐LluchA(November 26th2014). Materials for Central Nervous System Tissue Engineering Cells and Biomaterials in Regenerative Medicine Daniel Eberli IntechOpen DOI: 10.5772/59339Wang, Y., Wei, Y. T., Zu, Z. H., Ju, R. K., Guo, M. Y., Wang, X. M., … Cui, F. Z. (2011). Combination of Hyaluronic Acid Hydrogel Scaffold and PLGA Microspheres for Supporting Survival of Neural Stem Cells. Pharmaceutical Research, 28(6), 1406-1414. doi:10.1007/s11095-011-0452-3Nih, L. R., Moshayedi, P., Llorente, I. L., Berg, A. R., Cinkornpumin, J., Lowry, W. E., … Carmichael, S. T. (2017). Engineered HA hydrogel for stem cell transplantation in the brain: Biocompatibility data using a design of experiment approach. Data in Brief, 10, 202-209. doi:10.1016/j.dib.2016.11.069Nih, L. R., Gojgini, S., Carmichael, S. T., & Segura, T. (2018). Dual-function injectable angiogenic biomaterial for the repair of brain tissue following stroke. Nature Materials, 17(7), 642-651. doi:10.1038/s41563-018-0083-8Lin, R., & Iacovitti, L. (2015). Classic and novel stem cell niches in brain homeostasis and repair. Brain Research, 1628, 327-342. doi:10.1016/j.brainres.2015.04.029Ruddy, R. M., & Morshead, C. M. (2017). Home sweet home: the neural stem cell niche throughout development and after injury. Cell and Tissue Research, 371(1), 125-141. doi:10.1007/s00441-017-2658-0Mora-Lee, S., Sirerol-Piquer, M. S., Gutiérrez-Pérez, M., Gomez-Pinedo, U., Roobrouck, V. D., López, T., … García-Verdugo, J. M. (2012). Therapeutic Effects of hMAPC and hMSC Transplantation after Stroke in Mice. PLoS ONE, 7(8), e43683. doi:10.1371/journal.pone.0043683Boisserand, L. S. B., Kodama, T., Papassin, J., Auzely, R., Moisan, A., Rome, C., & Detante, O. (2016). Biomaterial Applications in Cell-Based Therapy in Experimental Stroke. Stem Cells International, 2016, 1-14. doi:10.1155/2016/6810562Adams, A. M., Arruda, E. M., & Larkin, L. M. (2012). Use of adipose-derived stem cells to fabricate scaffoldless tissue-engineered neural conduits in vitro. Neuroscience, 201, 349-356. doi:10.1016/j.neuroscience.2011.11.004Le Friec, A., Salabert, A.-S., Davoust, C., Demain, B., Vieu, C., Vaysse, L., … Loubinoux, I. (2017). Enhancing Plasticity of the Central Nervous System: Drugs, Stem Cell Therapy, and Neuro-Implants. Neural Plasticity, 2017, 1-9. doi:10.1155/2017/2545736Traystman, R. J. (2003). Animal Models of Focal and Global Cerebral Ischemia. ILAR Journal, 44(2), 85-95. doi:10.1093/ilar.44.2.85Doeppner, T. R., Kaltwasser, B., Teli, M. K., Sanchez-Mendoza, E. H., Kilic, E., Bähr, M., & Hermann, D. M. (2015). Post-stroke transplantation of adult subventricular zone derived neural progenitor cells — A comprehensive analysis of cell delivery routes and their underlying mechanisms. Experimental Neurology, 273, 45-56. doi:10.1016/j.expneurol.2015.07.023Karatas, H., Erdener, S. E., Gursoy-Ozdemir, Y., Gurer, G., Soylemezoglu, F., Dunn, A. K., & Dalkara, T. (2011). Thrombotic distal middle cerebral artery occlusion produced by topical FeCl3 application: A novel model suitable for intravital microscopy and thrombolysis studies. Journal of Cerebral Blood Flow & Metabolism, 31(6), 1452-1460. doi:10.1038/jcbfm.2011.8Karatas, H., Eun Jung, J., Lo, E. H., & van Leyen, K. (2018). Inhibiting 12/15-lipoxygenase to treat acute stroke in permanent and tPA induced thrombolysis models. Brain Research, 1678, 123-128. doi:10.1016/j.brainres.2017.10.024Zhou, F., Gao, S., Wang, L., Sun, C., Chen, L., Yuan, P., … Chen, X. (2015). Human adipose-derived stem cells partially rescue the stroke syndromes by promoting spatial learning and memory in mouse middle cerebral artery occlusion model. Stem Cell Research & Therapy, 6(1). doi:10.1186/s13287-015-0078-1Mora-Lee, S., Sirerol-Piquer, M. S., Gutiérrez-Pérez, M., López, T., Casado-Nieto, M., Jauquicoam, C., … García-Verdugo, J.-M. (2011). Histological and ultrastructural comparison of cauterization and thrombosis stroke models in immune-deficient mice. Journal of Inflammation, 8(1), 28. doi:10.1186/1476-9255-8-2

The RNA Polymerase II Factor RPAP1 Is Critical for Mediator-Driven Transcription and Cell Identity

The RNA polymerase II-associated protein 1 (RPAP1) is conserved across metazoa and required for stem cell differentiation in plants; however, very little is known about its mechanism of action or its role in mammalian cells. Here, we report that RPAP1 is essential for the expression of cell identity genes and for cell viability. Depletion of RPAP1 triggers cell de-differentiation, facilitates reprogramming toward pluripotency, and impairs differentiation. Mechanistically, we show that RPAP1 is essential for the interaction between RNA polymerase II (RNA Pol II) and Mediator, as well as for the recruitment of important regulators, such as the Mediator-specific RNA Pol II factor Gdown1 and the C-terminal domain (CTD) phosphatase RPAP2. In agreement, depletion of RPAP1 diminishes the loading of total and Ser5-phosphorylated RNA Pol II on many genes, with super-enhancer-driven genes among the most significantly downregulated. We conclude that Mediator/RPAP1/RNA Pol II is an ancient module, conserved from plants to mammals, critical for establishing and maintaining cell identity.We are grateful to Elisa Varela for assistance with morula and blastocyst fixa- tion. Work in the laboratory of M.S. is funded by the CNIO and the IRB and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (ERDF) (SAF2013-48256-R), the European Research Co uncil (ERC-2014-AdG/66 9622), the Region al Government of Ma- drid co-funded by the Euro pean Social Fund (ReCaRe project), the Euro pean Union (RISK-IR project), the Botin Foundation and Banco Santander (Santander Universities Glo bal Division), the Ramon Areces Found ation, and the AXA Foundation. S.R. was funded by a contract from the Ramon y Cajal Program(RYC-2011-09242) and by the Spanish Ministry of Economy co- funded by the ERDF (SAF2013-49147- P and SAF2016-80874-PS

High Diversity of vacA and cagA Helicobacter pylori Genotypes in Patients with and without Gastric Cancer

BACKGROUND: Helicobacter pylori is associated with chronic gastritis, peptic ulcers, and gastric cancer. The aim of this study was to assess the topographical distribution of H. pylori in the stomach as well as the vacA and cagA genotypes in patients with and without gastric cancer. METHODOLOGY/PRINCIPAL FINDINGS: Three gastric biopsies, from predetermined regions, were evaluated in 16 patients with gastric cancer and 14 patients with dyspeptic symptoms. From cancer patients, additional biopsy specimens were obtained from tumor centers and margins; among these samples, the presence of H. pylori vacA and cagA genotypes was evaluated. Positive H. pylori was 38% and 26% in biopsies obtained from the gastric cancer and non-cancer groups, respectively (p = 0.008), and 36% in tumor sites. In cancer patients, we found a preferential distribution of H. pylori in the fundus and corpus, whereas, in the non-cancer group, the distribution was uniform (p = 0.003). A majority of the biopsies were simultaneously cagA gene-positive and -negative. The fundus and corpus demonstrated a higher positivity rate for the cagA gene in the non-cancer group (p = 0.036). A mixture of cagA gene sizes was also significantly more frequent in this group (p = 0.003). Ninety-two percent of all the subjects showed more than one vacA gene genotype; s1b and m1 vacA genotypes were predominantly found in the gastric cancer group. The highest vacA-genotype signal-sequence diversity was found in the corpus and 5 cm from tumor margins. CONCLUSION/SIGNIFICANCE: High H. pylori colonization diversity, along with the cagA gene, was found predominantly in the fundus and corpus of patients with gastric cancer. The genotype diversity observed across systematic whole-organ and tumor sampling was remarkable. We find that there is insufficient evidence to support the association of one isolate with a specific disease, due to the multistrain nature of H. pylori infection shown in this work

c-Abl tyrosine kinase down-regulation as target for memory improvement in Alzheimer’s disease

BackgroundGrowing evidence suggests that the non-receptor tyrosine kinase, c-Abl, plays a significant role in the pathogenesis of Alzheimer’s disease (AD). Here, we analyzed the effect of c-Abl on the cognitive performance decline of APPSwe/PSEN1ΔE9 (APP/PS1) mouse model for AD.MethodsWe used the conditional genetic ablation of c-Abl in the brain (c-Abl-KO) and pharmacological treatment with neurotinib, a novel allosteric c-Abl inhibitor with high brain penetrance, imbued in rodent’s chow.ResultsWe found that APP/PS1/c-Abl-KO mice and APP/PS1 neurotinib-fed mice had improved performance in hippocampus-dependent tasks. In the object location and Barnes-maze tests, they recognized the displaced object and learned the location of the escape hole faster than APP/PS1 mice. Also, APP/PS1 neurotinib-fed mice required fewer trials to reach the learning criterion in the memory flexibility test. Accordingly, c-Abl absence and inhibition caused fewer amyloid plaques, reduced astrogliosis, and preserved neurons in the hippocampus.DiscussionOur results further validate c-Abl as a target for AD, and the neurotinib, a novel c-Abl inhibitor, as a suitable preclinical candidate for AD therapies

Ciencia Odontológica 2.0

Libro que muestra avances de la Investigación Odontológica en MéxicoEs para los integrantes de la Red de Investigación en Estomatología (RIE) una enorme alegría presentar el segundo de una serie de 6 libros sobre casos clínicos, revisiones de la literatura e investigaciones. La RIE está integrada por cuerpos académicos de la UAEH, UAEM, UAC y UdeG

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale

Caracterización funcional de la proteína adaptadora Sur8

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Celular. Fecha de lectura: 21-07-2010Las proteínas adaptadoras aseguran la fidelidad y eficiencia de la señal de transducción gracias a la unión de componentes de la ruta de señalización. Sur8 fue descubierta mediante ensayos genéticos en C. elegans y se caracterizó como una proteína adaptadora implicada en la señalización positiva de la ruta Ras/Raf/MEK/Erk. En esta tesis mostramos que la sobreexpresión de Sur8 aumenta la duración de la activación de Erk y promueve la diferenciación de células PC12 en respuesta EGF, estímulo que, condiciones normales, promueve proliferación. Además, demostramos que la depleción de Sur8 provoca una reducción de la fosforilación de Erk, lo cual provoca una inhibición de la formación de neuritas en células PC12 tratadas con NGF. Trabajos previos sugieren que la distribución de las isoformas de Ras en diferentes microdominios de la membrana plasmática y sistemas de endomembranas favorece una determinada interacción de Ras con sus efectores o reguladores, afectando a la duración e intensidad de la señal de transducción. En esta tesis mostramos que la localización de Sur8 en regiones de balsas lipídicas inhibe la fosforilación de Erk, la formación de focos transformantes y la neuritogénesis de células PC12, mientras que la localización de Sur8 en regiones de membrana desorganizada potencia la activación de Erk. Hemos mostrado también que Sur8 interacciona con otras proteínas implicadas en la ruta Ras/Raf/MEK/Erk como son B-Raf o Sprouty2, lo cual aporta nuevas teorías acerca del mecanismo de actuación de Sur8. Abstract Scaffold proteins ensure the fidelity and efficiency of signal transduction by joining the pathway components. Sur8 was discovered in a genetic study in C. Elegans and was caracterized as a scaffold protein that positively regulate the Ras/Raf/MEK/Erk pathway. In this thesis we demonstrate that Sur8 overexpresion enhances Erk activation duration and promote biological outcomes such as PC12 cells differentiation in response to EGF, a stimuli that promote proliferation under normal conditions. Furthemore, we demonstrate that Sur8 knockdown reduces Erk phosphorylation and inhibits NGF neurite outgrowth of PC12 cells. Previous works suggest that Ras distribution among different membrane microdomains and endomembranes, facilitates Ras interaction with its effectors or regulator proteins, affecting to the intensity and duration of signal transduction. In this thesis we show that Sur8 localized in lipid rafts inhibits Erk phosphorilation, transforming focci formation and PC12 cells neuritogenesis, whereas Sur8 localized in disordered membrana enhances Erk activation. We have also show that Sur8 interacts with other proteins of the Ras/Raf/MEK/Erk pathway such as B-Raf o Sprouty2, supporting new theories about Sur8 functional mechanism