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

Li, Xuri; Pontén, Annica; Aase, Karin; Karlsson, Linda; Abramsson, Alexandra; Uutela, Marko; Bäckström, G.; Hellström, Mats; Boström, Hans; Li, Hong; Soriano, Philippe; Betsholtz, Christer; Heldin, Carl‐Henrik; Alitalo, Kari; Östman, Arne; Eriksson, Ulf

doi:10.1038/35010579

Cited by 537 publications

(563 citation statements)

References 39 publications

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“…Both of these peptides require extracellular proteolytic cleavage to release the biologically active GFD (designated PDGF-CC and -DD). The GFD of PDGF-C and -D share significant homology with one another (approximately 50%) and with the previously described PDGF (20 to 23%) (7,8).…”

mentioning

confidence: 52%

Exogenous PDGF-D Is a Potent Mesangial Cell Mitogen and Causes a Severe Mesangial Proliferative Glomerulopathy

Hudkins

Gilbertson²,

Carling³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. The PDGF family consists of at least four members, PDGF-A, -B, -C, and -D. All of the PDGF isoforms bind and signal through two known receptors, PDGF receptor-␣ and PDGF receptor-␤, which are constitutively expressed in the kidney and are upregulated in specific diseases. It is well established that PDGF-B plays a pivotal role in the mediation of glomerular mesangial cell proliferation. However, little is known of the roles of the recently discovered PDGF-C and -D in mediating renal injury. In this study, adenovirus constructs encoding PDGF-B, -C, and -D were injected into mice. Mice with high circulating levels of PDGF-D developed a severe mesangial proliferative glomerulopathy, characterized by enlarged glomeruli and a striking increase in glomerular cellularity. The PDGF-B-overexpressing mice had a milder proliferative glomerulopathy, whereas the mice overexpressing PDGF-C and those that received adenovirus alone showed no measurable response. Mitogenicity of PDGF-D and -B for mesangial cells was confirmed in vitro. These findings emphasize the importance of engagement of PDGF receptor-␤ in transducing mesangial cell proliferation and demonstrate that PDGF-D is a major mediator of mesangial cell proliferation. Finally, this approach has resulted in a unique and potentially valuable model of mesangial proliferative glomerulopathy and its resolution.

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mentioning

confidence: 52%

Exogenous PDGF-D Is a Potent Mesangial Cell Mitogen and Causes a Severe Mesangial Proliferative Glomerulopathy

Hudkins

Gilbertson²,

Carling³

et al. 2004

Journal of the American Society of Nephrology

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“…This cleavage of the CUB domain results in the appearance of a 23-kd (PDGF-C) and a 32-kd (PDGF-D) protein under reducing conditions, representing the "core" growth factor domain monomers (2)(3)(4)25). Although the respective bands were usually absent in the case of PDGF-C, active PDGF-D could be detected in all SM samples investigated (at the predicted molecular mass of 32 kd) and showed a significantly higher expression in RA SM.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, PDGF-C may contribute to fibrotic processes, since the hearts of PDGF-C-transgenic mice exhibit a progressive hypertrophy with strong proliferation of cardiac fibroblasts (2).…”

mentioning

confidence: 99%

Expression of platelet‐derived growth factors C and D in the synovial membrane of patients with rheumatoid arthritis and osteoarthritis

Pohlers

Huber

Ukena

et al. 2006

Arthritis & Rheumatism

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“…However, when PDGF-C and PDGF-D were discovered, new insights into this growth factor family were gained (Li et al, 2000;Bergsten et al, 2001;LaRochelle et al, 2001). In addition to a conserved growth factor domain (GFD), shared by all four members, PDGF-C and PDGF-D contain an N-terminal CUB domain (Bork and Beckmann, 1993) within the full-length (fl) protein.…”

Section: Introductionmentioning

confidence: 99%

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

Ehnman

Fredriksson

et al. 2008

Oncogene

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

Cited by 537 publications

References 39 publications

Exogenous PDGF-D Is a Potent Mesangial Cell Mitogen and Causes a Severe Mesangial Proliferative Glomerulopathy

Exogenous PDGF-D Is a Potent Mesangial Cell Mitogen and Causes a Severe Mesangial Proliferative Glomerulopathy

Expression of platelet‐derived growth factors C and D in the synovial membrane of patients with rheumatoid arthritis and osteoarthritis

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

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