The predicted platelet-derived growth factor-C (PDGF-C) polypeptide contains an N-terminal CUB-like domain and a C-terminal domain with homology to members of the PDGF/vascular endothelial growth factor (VEGF) family. PDGF-C mRNA is widely expressed in normal tissues and does not appear to be up-regulated in the tumor cell lines tested. The PDGF-C gene was mapped to human chromosome 4q31-32. PDGF-C protein and the CUB domain of PDGF-C expressed in Escherichia coli, were able to stimulate proliferation of human artery smooth muscle cells, but were inactive on umbilical vein endothelial cells, osteoblasts, fibroblasts, skeletal muscle cells (SkMC), bovine chondrocytes, and rat myocardium cells. Although the mitogenic activity of PDGF-C and the CUB domain was only observed at concentrations ranging from 1 to 10 microg/ml, substitution of Cys(124) by Ser or deletion of Cys(124) significantly reduced the mitogenic activity. Our data suggest a possible role of the CUB domain of PDGF-C in addition to its role in maintaining latency of the PDGF domain.