Platelet-derived growth factor (PDGF) is a critical regulator of mesenchymal cell migration and proliferation. The vital functions of PDGFs for angiogenesis, as well as development of kidney, brain, cardiovascular system and pulmonary alveoli during embryogenesis, have been well demonstrated by gene knock-out approaches. Clinical studies reveal that aberrant expression of PDGF and its receptor is often associated with a variety of disorders including atherosclerosis, fibroproliferative diseases of lungs, kidneys and joints, and neoplasia. PDGF contributes to cancer development and progression by both autocrine and paracrine signaling mechanisms. In this review article, important features of the PDGF isoforms and their cell surface receptor subunits are discussed, with regards to signal transduction, PDGF-isoform specific cellular responses, and involvement in angiogensis, and tumorstromal interactions.

ABSTRACT

Platelet-derived growth factors (PDGFs) regulate a diverse array of cellular processes, including cell proliferation, transformation, migration, survival, and apoptosis of mesenchymal cells, in development as well as during pathogenesis (reviewed in references 31 and 42). For over 2 decades, PDGFs were thought to exist as the homodimers PDGF AA and BB or the heterodimer PDGF AB. These PDGF dimers are processed intracellularly and secreted as active dimers that readily activate PDGF receptors (PDGFRs). Recently, two new PDGF ligands (PDGF CC and DD) were discovered that have a unique two-domain structure with an N-terminal complement subcomponent C1r/C1s, Uegf, Bmp1 (CUB) domain and a C-terminal PDGF/vascular endothelial growth factor domain. PDGF CC and DD are secreted as full-length, latent dimers, and the proteolytic removal of the CUB domain is required for the growth factor domain of PDGF CC or DD to activate the PDGF receptors (4,20,21).PDGFs exert their biological functions through the activation of dimeric receptors made up of two structurally similar protein-tyrosine kinase receptor subunits (␣␣-, ␣␤-, or ␤␤-

Increasing evidence indicates the significance of platelet-derived growth factor receptor-b (b-PDGFR) signaling in prostate cancer (PCa). Accordingly, preclinical studies suggest the potential of b-PDGFR as a therapeutic target in metastatic PCa. However, a ligand responsible for b-PDGFR activation in PCa was unknown, and recent clinical trials with imatinib mesylate showed limited success due to normal tissue toxicity. Similarly, in spite of mounting evidence indicating the significance of matriptase in PCa, little is known about its substrates or molecular actions during PCa progression. Here, we identified PDGF-D as a ligand for b-PDGFR in PCa and discovered matriptase as its regulator. Matriptase activates PDGF-D by proteolytic removal of the CUB domain in a 2-step process, creating a hemidimer, followed by growth factor domain dimer (GFD-D) generation. Matriptase can deactivate PDGF-D by further proteolytic cleavage within the GFD, revealing its biphasic regulation. Importantly, PDGF-D/matriptase colocalization is accompanied with b-PDGFR phosphorylation in human PCa tissues. This study unveiled a novel signaling axis of matriptase/PDGF-D/b-PDGFR in PCa, providing new insights into functional interplay between serine protease and growth factor signaling networks.