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The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth

Oncogene volume 28, pages 534–544 (2009)Cite this article

Abstract

Members of the platelet-derived growth factor (PDGF) family are mitogens for cells of mesenchymal origin and have important functions during embryonic development, blood vessel maturation, fibrotic diseases and cancer. In contrast to the two classical PDGFs, the novel and less well-characterized members, PDGF-CC and PDGF-DD, are latent factors that need to be processed extracellularly by activating proteases, before they can mediate PDGF receptor activation. Here, we elucidate the structural requirements for urokinase plasminogen activator (uPA)-mediated activation of PDGF-DD, as well as the intricate interplay with uPA receptor (uPAR) signalling. Furthermore, we show that activated PDGF-DD, in comparison to latent, more potently transforms NIH/3T3 cells in vitro. Conversely, xenograft studies in nude mice demonstrate that cells expressing latent PDGF-DD are more tumorigenic than those expressing activated PDGF-DD. These findings imply that a fine-tuned proteolytic activation, in the local milieu, controls PDGF-DD bioavailability. Moreover, we suggest that proteolytic activation of PDGF-DD reveals a retention motif mediating interactions with pericellular components. Our proposed mechanism, where uPA not only generates active PDGF-DD, but also regulates its spatial distribution, provides novel insights into the biological function of PDGF-DD.

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References

  • United Kingdom Co-ordinating Committee on Cancer Research (1998). United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) Guidelines for the welfare of animals in experimental neoplasia (Second edition). Br J Cancer 77: 1–10.

    Google Scholar 

  • Bergsten E, Uutela M, Li X, Pietras K, Ostman A, Heldin CH et al. (2001). PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. Nat Cell Biol 3: 512–516.

    Article  CAS  Google Scholar 

  • Boehm T, Folkman J, Browder T, O'Reilly MS . (1997). Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390: 404–407.

    Article  CAS  Google Scholar 

  • Bork P, Beckmann G . (1993). The CUB domain. A widespread module in developmentally regulated proteins. J Mol Biol 231: 539–545.

    Article  CAS  Google Scholar 

  • Carmeliet P, Ng YS, Nuyens D, Theilmeier G, Brusselmans K, Cornelissen I et al. (1999). Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nat Med 5: 495–502.

    Article  CAS  Google Scholar 

  • Fredriksson L, Ehnman M, Fieber C, Eriksson U . (2005). Structural requirements for activation of latent platelet-derived growth factor CC by tissue plasminogen activator. J Biol Chem 280: 26856–26862.

    Article  CAS  Google Scholar 

  • Fredriksson L, Li H, Fieber C, Li X, Eriksson U . (2004). Tissue plasminogen activator is a potent activator of PDGF-CC. EMBO J 23: 3793–3802.

    Article  CAS  Google Scholar 

  • Grunstein J, Masbad JJ, Hickey R, Giordano F, Johnson RS . (2000). Isoforms of vascular endothelial growth factor act in a coordinate fashion to recruit and expand tumor vasculature. Mol Cell Biol 20: 7282–7291.

    Article  CAS  Google Scholar 

  • Heldin CH, Westermark B . (1999). Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79: 1283–1316.

    Article  CAS  Google Scholar 

  • Hoyer-Hansen G, Ronne E, Solberg H, Behrendt N, Ploug M, Lund LR et al. (1992). Urokinase plasminogen activator cleaves its cell surface receptor releasing the ligand-binding domain. J Biol Chem 267: 18224–18229.

    CAS  PubMed  Google Scholar 

  • Irigoyen JP, Munoz-Canoves P, Montero L, Koziczak M, Nagamine Y . (1999). The plasminogen activator system: biology and regulation. Cell Mol Life Sci 56: 104–132.

    Article  CAS  Google Scholar 

  • Ke SH, Coombs GS, Tachias K, Navre M, Corey DR, Madison EL . (1997). Distinguishing the specificities of closely related proteases. Role of P3 in substrate and inhibitor discrimination between tissue-type plasminogen activator and urokinase. J Biol Chem 272: 16603–16609.

    Article  CAS  Google Scholar 

  • Kiyan J, Kiyan R, Haller H, Dumler I . (2005). Urokinase-induced signaling in human vascular smooth muscle cells is mediated by PDGFR-beta. EMBO J 24: 1787–1797.

    Article  CAS  Google Scholar 

  • LaRochelle WJ, Jeffers M, Corvalan JR, Jia XC, Feng X, Vanegas S et al. (2002). Platelet-derived growth factor D: tumorigenicity in mice and dysregulated expression in human cancer. Cancer Res 62: 2468–2473.

    CAS  PubMed  Google Scholar 

  • LaRochelle WJ, Jeffers M, McDonald WF, Chillakuru RA, Giese NA, Lokker NA et al. (2001). PDGF-D, a new protease-activated growth factor. Nat Cell Biol 3: 517–521.

    Article  CAS  Google Scholar 

  • LaRochelle WJ, May-Siroff M, Robbins KC, Aaronson SA . (1991). A novel mechanism regulating growth factor association with the cell surface: identification of a PDGF retention domain. Genes Dev 5: 1191–1199.

    Article  CAS  Google Scholar 

  • Lee S, Jilani SM, Nikolova GV, Carpizo D, Iruela-Arispe ML . (2005). Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol 169: 681–691.

    Article  CAS  Google Scholar 

  • Li H, Fredriksson L, Li X, Eriksson U . (2003). PDGF-D is a potent transforming and angiogenic growth factor. Oncogene 22: 1501–1510.

    Article  CAS  Google Scholar 

  • Li X, Ponten A, Aase K, Karlsson L, Abramsson A, Uutela M et al. (2000). PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor. Nat Cell Biol 2: 302–309.

    Article  CAS  Google Scholar 

  • Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellstrom M et al. (2003). Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 17: 1835–1840.

    Article  CAS  Google Scholar 

  • Liu D, Aguirre Ghiso J, Estrada Y, Ossowski L . (2002). EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell 1: 445–457.

    Article  CAS  Google Scholar 

  • Miyake H, Hara I, Yamanaka K, Gohji K, Arakawa S, Kamidono S . (1999). Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer. Prostate 39: 123–129.

    Article  CAS  Google Scholar 

  • Mondino A, Blasi F . (2004). uPA and uPAR in fibrinolysis, immunity and pathology. Trends Immunol 25: 450–455.

    Article  CAS  Google Scholar 

  • Olofsson B, Pajusola K, von Euler G, Chilov D, Alitalo K, Eriksson U . (1996). Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform. J Biol Chem 271: 19310–19317.

    Article  CAS  Google Scholar 

  • Ostman A, Andersson M, Betsholtz C, Westermark B, Heldin CH . (1991). Identification of a cell retention signal in the B-chain of platelet-derived growth factor and in the long splice version of the A-chain. Cell Regul 2: 503–512.

    Article  CAS  Google Scholar 

  • Simon DI, Wei Y, Zhang L, Rao NK, Xu H, Chen Z et al. (2000). Identification of a urokinase receptor-integrin interaction site. Promiscuous regulator of integrin function. J Biol Chem 275: 10228–10234.

    Article  CAS  Google Scholar 

  • Ustach CV, Kim HR . (2005). Platelet-derived growth factor D is activated by urokinase plasminogen activator in prostate carcinoma cells. Mol Cell Biol 25: 6279–6288.

    Article  CAS  Google Scholar 

  • Xu L, Tong R, Cochran DM, Jain RK . (2005). Blocking platelet-derived growth factor-D/platelet-derived growth factor receptor beta signaling inhibits human renal cell carcinoma progression in an orthotopic mouse model. Cancer Res 65: 5711–5719.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Carl-Henrik Heldin (Ludwig Institute for Cancer Research Ltd, Uppsala Branch) for kindly providing PAE cell lines, R33 antiserum against human PDGFRβ and purified PDGF-BB protein. Soheilla Rezaian and Sara Cunha helpfully assisted with PDGF-DD protein purification and tissue preparations; Erika Folestad and Christina Fieber generously provided us with human PDGF-D and VEGF-B plasmids. The Swedish Cancer Foundation, the Swedish Research Council, the Novo Nordisk Foundation and Karolinska Institutet supported this study.

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  1. Ludwig Institute for Cancer Research Ltd, Stockholm Branch, Stockholm, Sweden

    M Ehnman, H Li, L Fredriksson, K Pietras & U Eriksson

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  1. M Ehnman
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  2. H Li
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  3. L Fredriksson
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  4. K Pietras
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Correspondence to U Eriksson.

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Ehnman, M., Li, H., Fredriksson, L. et al. The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth. Oncogene 28, 534–544 (2009). https://doi.org/10.1038/onc.2008.410

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