Center for Human Genetics euven

Leuven, Belgium

Center for Human Genetics euven

Leuven, Belgium

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Esselens C.,University of Barcelona | Esselens C.,Center for Human Genetics euven | Malapeira J.,University of Barcelona | Colome N.,University of Barcelona | And 7 more authors.
Journal of Biological Chemistry | Year: 2010

Metastasis is a sequential process that allows cells to move from the primary tumor and grow elsewhere. Because of their ability to cleave a variety of extracellular signaling and adhesion molecules, metalloproteases have been long considered key components of the metastatic program. However, the function of certain metalloproteases, such as ADAMTS1, is not clear and seems to depend on the cellular environment and/or the stage of tumor progression. To characterize the function of ADAMTS1, we performed two alternative proteomic approaches, difference gel electrophoresis and stable isotope labeling by amino acids in cell culture, to identify novel substrates of the metalloprotease. Both techniques showed that overexpression of ADAMTS1 leads to the release of semaphorin 3C from the extracellular matrix. Although semaphorins are well known regulators of axon guidance, accumulating evidence shows that they may also participate in tumor progression. Here, we show that the cleavage of semaphorin 3C induced by ADAMTS1 promotes the migration of breast cancer cells, indicating that the co-expression of these molecules in tumors may contribute to the metastatic program. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Thimiri Govinda Raj D.B.,Center for Human Genetics euven | Thimiri Govinda Raj D.B.,IMEC | Ghesquiere B.,Vlaams Institute for Biotechnology | Tharkeshwar A.K.,Center for Human Genetics euven | And 12 more authors.
Molecular Systems Biology | Year: 2011

We manufactured a novel type of lipid-coated superparamagnetic nanoparticles that allow for a rapid isolation of plasma membranes (PMs), enabling high-resolution proteomic, glycomic and lipidomic analyses of the cell surface. We used this technology to characterize the effects of presenilin knockout on the PM composition of mouse embryonic fibroblasts. We found that many proteins are selectively downregulated at the cell surface of presenilin knockout cells concomitant with lowered surface levels of cholesterol and certain sphingomyelin species, indicating defects in specific endosomal transport routes to and/or from the cell surface. Snapshots of N-glycoproteomics and cell surface glycan profiling further underscored the power and versatility of this novel methodology. Since PM proteins provide many pathologically relevant biomarkers representing two-thirds of the currently used drug targets, this novel technology has great potential for biomedical and pharmaceutical applications. © 2011 EMBO and Macmillan Publishers Limited All rights reserved.


Rajendran L.,University of Zürich | Annaert W.,Center for Human Genetics euven
Traffic | Year: 2012

Membrane proteins are constantly being trafficked in cells and the relevant proteins in Alzheimer's disease (AD), such as the amyloid precursor protein (APP) and its processing enzymes, are not exempted from that. Molecular cell biologists have been endeavoring to ascertain a roadmap for APP processing and trafficking in various cell types including neurons. This has led to the identification of numerous regulatory sorting mechanisms, protein-protein interactions and lipidic microenvironments that largely define how and where the substrate APP meets its processing enzymes. However, the cell biology of tau, and the formation of neurofibrillary tangles, has long been regarded as a separate field. Nonetheless, recent progress is bringing both worlds together in a new paradigm on how Aβ toxicity and tau are physiologically connected. Here, we discuss an update of our current appraisal on how membrane trafficking may play an important role in the pathogenesis of the disease and how this could be exploited for effective therapy. © 2012 John Wiley & Sons A/S.


Malapeira J.,University of Barcelona | Esselens C.,University of Barcelona | Esselens C.,Center for Human Genetics euven | Bech-Serra J.J.,University of Barcelona | And 4 more authors.
Oncogene | Year: 2011

The activity of a variety of extracellular signaling factors is tightly regulated by proteins containing A Disintegrin And a Metalloprotease domain (ADAM) metalloproteases through limited proteolysis. Thus, the identification of ADAM substrates may unveil novel components and mechanisms of cell signaling pathways. We report the identification of the transmembrane protein vasorin (VASN), a transforming growth factor-Β (TGFΒ) trap, as a substrate of ADAM17. The metalloprotease efficiently generates a soluble fragment encompassing the extracellular domain of VASN. Despite the importance of TGFΒ in normal development and tumor progression, the regulation of VASN is completely unknown. Here, we show that only the soluble form of VASN inhibits TGFΒ and that the secretion of VASN is tightly controlled by ADAM17. Hence, inhibition of ADAM17 leads to the upregulation of TGFΒ signaling. Adding a new level of complexity to the function of ADAM17, we finally show that, through the cleavage of VASN, the metalloprotease controls TGFΒ-mediated epithelial-to-mesenchymal transition. © 2011 Macmillan Publishers Limited All rights reserved.

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