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Molecular and Cellular Biology, July 2005, p. 6279-6288, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.6279-6288.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Platelet-Derived Growth Factor D Is Activated by Urokinase Plasminogen Activator in Prostate Carcinoma Cells

Carolyn V. Ustach and Hyeong-Reh Choi Kim*

Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201

Received 12 October 2004/ Returned for modification 7 January 2005/ Accepted 15 April 2005

Platelet-derived growth factor (PDGF) protein family members are potent mitogens and chemoattractants for mesenchymal cells. The classic PDGF ligands A and B are single-domain protein chains which are secreted as active dimers capable of activating their cognate PDGF receptors (PDGFRs). In contrast to PDGFs A and B, PDGF D contains an N-terminal complement subcomponent C1r/C1s, Uegf, and Bmp1 (CUB) domain and a C-terminal PDGF domain. PDGF D must undergo extracellular proteolytic processing, separating the CUB domain from the PDGF domain, before the PDGF domain can stimulate ß-PDGFR-mediated cell signal transduction. Here, we report that prostate carcinoma cells LNCaP and PC3 autoactivate latent full-length PDGF D into its active form under serum-independent conditions and that this autoactivation is inhibited by PAI-1, a urokinase plasminogen activator (uPA)/tissue plasminogen activator (tPA) inhibitor. Interestingly, uPA, but not the closely related protease tPA, is capable of processing recombinant latent PDGF DD into the active form. We identify the uPA cleavage site between the CUB and PDGF domains of the full-length PDGF D by mutational analysis and show that PDGF D and uPA colocalize in human prostate carcinoma. This evidence provides a direct link between uPA- and PDGF D-mediated cell signaling, which may contribute to the progression of prostate cancer.

* Corresponding author. Mailing address: Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201. Phone: (313) 577-2407. Fax: (313) 577-0057. E-mail: hrckim{at}med.wayne.edu.

Molecular and Cellular Biology, July 2005, p. 6279-6288, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.6279-6288.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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