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Pellinen T.,University of Helsinki | Sanchez S.,Microscopy and Dynamic Imaging Unit | Sanchez S.,University of Concepcion | Wang Y.,University of Helsinki | And 2 more authors.
Developmental Cell

Nuclear membrane microdomains are proposed to act as platforms for regulation of nuclear function, but little is known about the mechanisms controlling their formation. Organization of the plasma membrane is regulated by actin polymerization, and the existence of an actin pool in the nucleus suggests that a similar mechanism might operate here. Weshow that nuclear membrane organization and morphology are regulated by the nuclear level of active Rac1 through actin polymerization-dependent mechanisms. Rac1 nuclear export is mediated by two internal nuclear export signals and through its interaction with nucleophosmin-1 (B23), which acts as a Rac1 chaperone inside the nucleus. Rac1 nuclear accumulation alters the balance between cytosolic Rac1 and Rho, increasing RhoA signaling in the cytoplasm and promoting a highly invasive phenotype. Nuclear Rac1 shuttling is a finely tuned mechanism for controlling nuclear shape and organization and cell invasiveness. © 2015 Elsevier Inc. Source

Goetz J.G.,CNRS Institute of Genetics and of Molecular and Cellular Biology | Samaniego R.,Hospital General Universitario Gregorio Maranon | Calvo E.,Proteomics Unit | Tello M.,CSIC - National Center of Microelectronics | And 5 more authors.

Mechanotransduction is a key determinant of tissue homeostasis and tumor progression. It is driven by intercellular adhesions, cell contractility, and forces generated within the microenvironment and is dependent on extracellular matrix composition, organization, and compliance. We show that caveolin-1 (Cav1) favors cell elongation in three-dimensional cultures and promotes Rho- and force-dependent contraction, matrix alignment, and microenvironment stiffening through regulation of p190RhoGAP. In turn, microenvironment remodeling by Cav1 fibroblasts forces cell elongation. Cav1-deficient mice have disorganized stromal tissue architecture. Stroma associated with human carcinomas and melanoma metastases is enriched in Cav1-expressing carcinoma-associated fibroblasts (CAFs). Cav1 expression in breast CAFs correlates with low survival, and Cav1 depletion in CAFs decreases CAF contractility. Consistently, fibroblast expression of Cav1, through p190RhoGAP regulation, favors directional migration and invasiveness of carcinoma cells in vitro. In vivo, stromal Cav1 remodels peri- and intratumoral microenvironments to facilitate tumor invasion, correlating with increased metastatic potency. Thus, Cav1 modulates tissue responses through force-dependent architectural regulation of the microenvironment. PaperFlick: © 2011 Elsevier Inc. Source

Altelaar A.F.M.,University Utrecht | Altelaar A.F.M.,Netherlands Proteomics Center | Munoz J.,University Utrecht | Munoz J.,Netherlands Proteomics Center | And 3 more authors.
Nature Reviews Genetics

Next-generation sequencing allows the analysis of genomes, including those representing disease states. However, the causes of most disorders are multifactorial, and systems-level approaches, including the analysis of proteomes, are required for a more comprehensive understanding. The proteome is extremely multifaceted owing to splicing and protein modifications, and this is further amplified by the interconnectivity of proteins into complexes and signalling networks that are highly divergent in time and space. Proteome analysis heavily relies on mass spectrometry (MS). MS-based proteomics is starting to mature and to deliver through a combination of developments in instrumentation, sample preparation and computational analysis. Here we describe this emerging next generation of proteomics and highlight recent applications. © 2013 Macmillan Publishers Limited. Source

Munoz J.,Proteomics Unit | Heck A.J.R.,University Utrecht
Angewandte Chemie - International Edition

A herculean task: Determining the human proteome sets the ultimate challenge in cell biology as it is thought to consist of more than 1000000 proteoforms in contrast to "only" 20000 protein-coding genes. Two teams of researchers have now proved the translation of 18000 proteins (and more than 27000 isoforms) by mass spectrometry. They obtained important information on the extent of protein translation and alternative splicing. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA Weinheim. Source

Lomsadze K.,Tbilisi State University | Salgado A.,CSIC - National Center for Metallurgical Research | Calvo E.,Proteomics Unit | Antonio Lopez J.,Proteomics Unit | Chankvetadze B.,Tbilisi State University

In our recent studies, the reversal of the enantiomer migration order (EMO) was observed with heptakis (2,3-dimethyl-6-sulfo)-β-CD (HDMS-β-CD) when aqueous electrolyte was changed with nonaqueous electrolyte in CE. One-dimensional rotating frame nuclear Overhauser effect spectroscopy experiments prevailed that an inclusion complex was formed between the analyte and the chiral selector in the aqueous buffer, whereas an external complex resulted when a methanolic electrolyte was employed. In the case of the similarly substituted heptakis (2,3-diacetyl-6-sulfo)-β-CD (HDAS-β-CD), the external complex was observed in the aqueous buffer but an inclusion complex was formed in methanolic electrolyte. In contrast to heptakis (2,3-dimethyl-6-sulfo)-β-CD, no reversal of the enantiomer migration order was observed with HDAS-β-CD. In the present study, further mechanisms of enantioselective recognition and separation of propranolol enantiomers with HDAS-β-CD were investigated by using different techniques of nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. To the best of our knowledge, enantioselective nuclear Overhauser effect was observed for the first time in this study. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

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