The endocytic receptor uPARAP is a regulator of extracellular thrombospondin-1
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Matrix Biology |
| Vol/bind | 111 |
| Sider (fra-til) | 307-328 |
| Antal sider | 22 |
| ISSN | 0945-053X |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
This study is supported by the Danish Medical Research Council (Grant Nos. 4092-00387B and DFF-4004-00340 ); the Danish Cancer Society (Grant Nos. R90-A5989 , R146-A9326-16-S2 , R231-A13832 , R231-A14035 , and R222-A13103 ); Simon Fougner Hartmanns family foundation; The Lundbeck Foundation (grant no. R307-2018-3326 ); Region Hovedstadens forskningsfond; The Novo Nordisk Foundation; Dansk Kræftforskningsfond. Proteomics and mass spectrometry research at SDU is supported by generous grants to the VILLUM Center for Bioanalytical Sciences (VILLUM Foundation grant no. 7292, to O.N.J .) and PRO-MS: Danish National Mass Spectrometry Platform for Functional Proteomics (grant no. 5072-00007B, to O.N.J. ). None of the funding sources had any role in the study design, in the collection, analysis or interpretation of data, in the writing of the article or in the decision to submit the article for publication.
Funding Information:
The excellent technical assistantance of Katharina Hassing, Mia Grønning Høg, Britt Kongstofte (Finsen Laboratory) and Andrea Lorentzen (University of Southern Denmark) is gratefully acknowledged. FACS of the CRISPR transfected SaOS-2 cells was conducted by Anna Fossum at the FACS facility at BRIC, University of Copenhagen. This study is supported by the Danish Medical Research Council (Grant Nos. 4092-00387B and DFF-4004-00340); the Danish Cancer Society (Grant Nos. R90-A5989, R146-A9326-16-S2, R231-A13832, R231-A14035, and R222-A13103); Simon Fougner Hartmanns family foundation; The Lundbeck Foundation (grant no. R307-2018-3326); Region Hovedstadens forskningsfond; The Novo Nordisk Foundation; Dansk Kræftforskningsfond. Proteomics and mass spectrometry research at SDU is supported by generous grants to the VILLUM Center for Bioanalytical Sciences (VILLUM Foundation grant no. 7292, to O.N.J.) and PRO-MS: Danish National Mass Spectrometry Platform for Functional Proteomics (grant no. 5072-00007B, to O.N.J.). None of the funding sources had any role in the study design, in the collection, analysis or interpretation of data, in the writing of the article or in the decision to submit the article for publication. All animal experiments were approved by the Danish Animal Experiments Inspectorate under the license 2020-15-0201-00765 granted to L. H. Engelholm.
Publisher Copyright:
© 2022 The Author(s)
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