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First published online 19 February 2008
doi: 10.1242/jcs.021006

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Extracellular matrix retention of thrombospondin 1 is controlled by its conserved C-terminal region

Josephine C. Adams^1,2,*, Amber A. Bentley¹, Marc Kvansakul^3,, Deborah Hatherley⁴ and Erhard Hohenester³

¹ Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
² Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
³ Division of Cell and Molecular Biology, Imperial College London, Biophysics Section, Blackett Laboratory, London, SW7 2AZ, UK
⁴ Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK

^* Author for correspondence (e-mail: adamsj{at}ccf.org)

Accepted 3 December 2007

Thrombospondins (TSPs) are an evolutionarily ancient family of extracellular calcium-binding glycoproteins. The five mammalian TSPs collectively have important roles in angiogenesis and vascular biology, synaptogenesis, wound repair and connective tissue organisation. Their complex functions relate to the multiple postsecretion fates of TSPs that can involve endocytic uptake, proteolysis or retention within the extracellular matrix (ECM). Surprisingly, the molecular and cellular mechanisms by which TSPs become retained within the ECM are poorly understood. We hypothesised that the highly conserved TSP C-terminal domain mediates ECM retention. We report that ECM incorporation as insoluble punctate deposits is an evolutionarily conserved property of TSPs. ECM retention of TSP1 is mediated by the C-terminal region in trimeric form, and not by C-terminal monomer or trimers of the N-terminal domain or type 1 repeats. Using a novel mRFP-tagged TSP1 C-terminal trimer, we demonstrate that ECM retention involves the RGD site and a novel site in the L-lectin domain with structural similarity to the ligand-binding site of cargo transport proteins. CD47 and β1 integrins are dispensable for ECM retention, but β1 integrins enhance activity. These novel data advance concepts of the molecular processes that lead to ECM retention of TSP1.

Key words: Thrombospondins, Extracellular matrix, Integrins, L-type lectin, Red fluorescent protein

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