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ADAM17 (TACE) regulates TGFβ signaling through the cleavage of vasorin

Oncogene volume 30, pages 1912–1922 (2011)Cite this article

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Abstract

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.

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Acknowledgements

We thank Dr Fernando López-Casillas for critical reading of the manuscript. The Proteomics Laboratory is a member of the National Spanish Institute for Proteomics (PROTEORED) and it is funded in part by Fundació Cellex. CW Esselens is a postdoctoral fellow from the Juan de la Cierva program (Spanish Ministry of Education). This research was supported by Grants from the Instituto de Salud Carlos III (Intrasalud PI081154 and the network of cooperative cancer research (RTICC-RD06/0020/0022) to JA and PI071058 to FC) and the Breast Cancer Research Foundation (BCRF).

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Author notes

  1. C Esselens

    Present address: 5Current address: Lab for Membrane Trafficking (VIB11), Center for Human Genetics KULeuven, Herestraat 49 bus 602, Leuven, Belgium.,

Authors and Affiliations

  1. Medical Oncology Research Program, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain

    J Malapeira, C Esselens & J Arribas

  2. Proteomics Laboratory, Research Institute Foundation and Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain

    J J Bech-Serra & F Canals

  3. Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Campus de la UAB, Bellaterra, Spain

    J Arribas

  4. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    J Arribas

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  1. J Malapeira
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Correspondence to J Arribas.

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Malapeira, J., Esselens, C., Bech-Serra, J. et al. ADAM17 (TACE) regulates TGFβ signaling through the cleavage of vasorin. Oncogene 30, 1912–1922 (2011). https://doi.org/10.1038/onc.2010.565

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