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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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Transmodulation of Cell Surface Regulatory Molecules via Ectodomain Shedding

Persio Dello Sbarba / Elisabetta Rovida

Citation Information: Biological Chemistry. Volume 383, Issue 1, Pages 69–83, ISSN (Print) 1431-6730, DOI: 10.1515/BC.2002.007, June 2005

Publication History

Published Online:
2005-06-01

Abstract

Cell responses to exogenous stimuli often result in a rapid decrease of cell surface density of a wide range of diverse regulatory proteins, receptor and adhesion molecules in particular. This decrease may occur in a liganddependent fashion (downregulation), following endocytosis and degradation by lysosomal proteases, or by downmodulation, where molecules are targeted by endoproteases directly on cell surface. These proteases are recruited by transmodulating agents, different from ligand, which act via their own receptors and the related intracellularlygenerated signals. Endoproteolytic activity determines the release of large portions (shedding) of substrate proteins, called ectodomains, which are usually not ligandbound, and therefore represent biologicallyactive molecules. Ectodomain shedding is involved in a number of pathophysiological processes, such as inflammation, cell degeneration and apoptosis, and oncogenesis. Common features of the process, such as the involvement of protein kinase C and of transmembrane metalloproteases, have been identified. In this review, we summarize basic concepts on downmodulation and ectodomain shedding, and provide an update of the issue with respect to: (i) new entries to the list of molecules found involved in the process; (ii) current views about the upstream control of shedding, i.e. the pathways linking the signals triggered by the transmodulating agents to the activation of endoproteolytic activity on the cell surface.

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