Proteolytic control of TGF-β co-receptor activity by BMP-1/tolloid-like proteases revealed by quantitative iTRAQ proteomics.

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Most of the growth factors activated by BMP-1 are members of the TGF-β superfamily known to regulate multiple biological processes including embryonic development, wound healing, inflammation and tumor progression. In this study, we used an iTRAQ (isobaric tags for relative and absolute quantification)-based quantitative proteomic approach to reveal the release of proteolytic fragments from the cell surface or the ECM by BMP-1. Thirty-eight extracellular proteins were found in significantly higher or lower amounts in the conditioned medium of HT1080 cells overexpressing BMP-1 and thus, could be considered as candidate substrates. Strikingly, three of these new candidates (betaglycan, CD109 and neuropilin-1) were TGF-β co-receptors, also acting as antagonists when released from the cell surface, and were chosen for further substrate validation. Betaglycan and CD109 proved to be directly cleaved by BMP-1 and the corresponding cleavage sites were extensively characterized using a new mass spectrometry approach. Furthermore, we could show that the ability of betaglycan and CD109 to interact with TGF-β was altered after cleavage by BMP-1, leading to increased and prolonged SMAD2 phosphorylation in BMP-1-overexpressing cells. Betaglycan processing was also observed in primary corneal keratocytes, indicating a general and novel mechanism by which BMP-1 directly affects signaling by controlling TGF-β co-receptor activity. The proteomic data have been submitted to ProteomeXchange with the identifier PXD000786 and doi: 10.6019/PXD000786 .", "claims": [{"id": "claim-target-result", "statement": "The paper used an iTRAQ-based quantitative proteomic approach to identify BMP-1-associated extracellular protein changes, with the proteomic source data submitted to ProteomeXchange (PXD000786; doi:10.6019/PXD000786).", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:25260970", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "In this study, we used an iTRAQ (isobaric tags for relative and absolute quantification)-based quantitative proteomic approach to reveal the release of proteolytic fragments from the cell surface or the ECM by BMP-1."}, {"asset": "source:pmid:25260970", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Thirty-eight extracellular proteins were found in significantly higher or lower amounts in the conditioned medium of HT1080 cells overexpressing BMP-1 and thus, could be considered as candidate substrates."}, {"asset": "source:pmid:25260970", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "The proteomic data have been submitted to ProteomeXchange with the identifier PXD000786 and doi:10.6019/PXD000786."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "The paper used an iTRAQ-based quantitative proteomic approach to identify BMP-1-associated extracellular protein changes, with the proteomic source data submitted to ProteomeXchange (PXD000786; doi:10.6019/PXD000786).", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:25260970"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "blocked", "blocked_on": "data:accession_absent", "description": "The GEO series accession resolves and its sample accessions are listed. 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