The endocytic receptor uPARAP is a regulator of extracellular thrombospondin-1.

Autor: Nørregaard KS; Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen, Denmark., Jürgensen HJ; Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen, Denmark., Ingvarsen SZ; Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen, Denmark., Heltberg SS; Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen, Denmark., Hagensen CE; Department of Biochemistry & Molecular Biology and VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, DK-5230 Odense, Denmark., Gårdsvoll H; Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen, Denmark., Madsen DH; National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte, DK-2730 Herlev, Denmark., Jensen ON; Department of Biochemistry & Molecular Biology and VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, DK-5230 Odense, Denmark., Engelholm LH; Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen, Denmark., Behrendt N; Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen, Denmark. Electronic address: niels.behrendt@finsenlab.dk.
Jazyk: angličtina
Zdroj: Matrix biology : journal of the International Society for Matrix Biology [Matrix Biol] 2022 Aug; Vol. 111, pp. 307-328. Date of Electronic Publication: 2022 Jul 22.
DOI: 10.1016/j.matbio.2022.07.004
Abstrakt: Thrombospondin-1 (TSP-1) is a matricellular protein with a multitude of functions in the pericellular and extracellular environment. We report a novel pathway for the regulation of extracellular TSP-1, governed by the endocytic collagen receptor, uPARAP (urokinase plasminogen activator receptor-associated protein; MRC2 gene product, also designated Endo180, CD280). First, using a novel proteomic approach for unbiased identification of ligands for endocytosis, we identify TSP-1 as a candidate ligand for specific uptake by uPARAP. We then show that uPARAP can efficiently internalize TSP-1 for lysosomal degradation, that this capability is not shared by other, closely related endocytic receptors and that uPARAP serves to regulate the extracellular levels of TSP-1 in vitro. Using wild type and uPARAP null mice, we also demonstrate uPARAP-mediated endocytosis of TSP-1 in dermal fibroblasts in vivo. Unlike other uPARAP ligands, the interaction with TSP-1 is sensitive to heparin and the responsible molecular motifs in uPARAP are overlapping, but not identical with those governing the interaction with collagens. Finally, we show that uPARAP can also mediate the endocytosis of TSP-2, a thrombospondin closely related to TSP-1, but not the more distantly related members of the same protein family, TSP-3, -4 and -5. These findings indicate that the role of uPARAP in ECM remodeling is not limited to the uptake of collagen for degradation but also includes an orchestrator function in the regulation of thrombospondins with numerous downstream effects. This is likely to be an important factor in the physiological and pathological roles of uPARAP in bone biology, fibrosis and cancer. The proteomic data has been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD031272.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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