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PDGF-C is a new protease-activated ligand for the PDGF α-receptor

Abstract

Platelet-derived growth factors (PDGFs) are important in many types of mesenchymal cell. Here we identify a new PDGF, PDGF-C, which binds to and activates the PDGF α-receptor. PDGF-C is activated by proteolysis and induces proliferation of fibroblasts when overexpressed in transgenic mice. In situ hybridization analysis in the murine embryonic kidney shows preferential expression of PDGF-C messenger RNA in the metanephric mesenchyme during epithelial conversion. Analysis of kidneys lacking the PDGF α-receptor shows selective loss of mesenchymal cells adjacent to sites of expression of PDGF-C mRNA; this is not found in kidneys from animals lacking PDGF-A or both PDGF-A and PDGF-B, indicating that PDGF-C may have a unique function.

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Figure 1: Amino-acid sequence and domain structure of human PDGF-C.
Figure 2: Expression and purification of full-length and core-domain PDGF-C.
Figure 3: The core domain of PDGF-CC, but not full-length PDGF-CC, is a high-affinity agonist for PDGFR-α.
Figure 4: Limited proteolysis of full-length PDGF-CC releases an active C-terminal PDGF/VEGF domain.
Figure 5: Transgenic expression of PDGF-C in mouse heart.
Figure 6: Expression of transcripts encoding PDGF-C and PDGF-A in human tissues.
Figure 7: Expression of PDGF-C, PDGF-A and PDGFR-α in the developing mouse kidney.
Figure 8: Loss of interstitial mesenchyme in kidneys lacking PDGFR-α, but not in those lacking PDGF-A or both PDGF-A and PDGF-B.

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Acknowledgements

We thank B. Åkerblom and C. Raynoschek for technical assistance, and U. Engström for synthesizing peptides. This study was supported by grants from the Swedish and Finnish Cancer Societies, the Swedish Medical Research Council, the Göran Gustafsson Foundation, the Inga-Britt and Arne Lundberg Foundation, the Swedish Heart and Lung Foundation and the Novo Nordisk Foundation. The cooperative research agreement between the Ludwig Institute for Cancer Research, Stockholm branch, and Fuji Photo Film (Europe) is gratefully acknowledged.

Correspondence and requests for materials should be addressed to U.E. The nucleotide and amino-acid sequences of human PDGF-C have been deposited at GenBank under accession number AF244813.

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Correspondence to Ulf Eriksson.

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Li, X., Pontén, A., Aase, K. et al. PDGF-C is a new protease-activated ligand for the PDGF α-receptor . Nat Cell Biol 2, 302–309 (2000). https://doi.org/10.1038/35010579

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