Platelet-derived growth factor (PDGF) receptor-α activates c-Jun NH2- terminal kinase-1 and antagonizes PDGF receptor-β-induced phenotypic transformation

Abstract

Platelet-derived growth factor (PDGF) is a potent mitogen for mesenchymal cells. The PDGF B-chain (c-sis proto-oncogene) homodimer (PDGF BB) and v-sis, its vital counterpart, activate both α- and β-receptor subunits (α-PDGFR and β-PDGFR) and mediate anchorage-independent growth in NIH3T3 cells. In contrast, the PDGF A chain homodimer (PDGF AA) activates α- PDGFR only and fails to induce phenotypic transformation. In the present study, we investigated α- and β-PDGFR specific signaling pathways that are responsible for the differences between the transforming ability of PDGF AA and BB. To study PDGF BB activation of β-PDGFR, we established NIH3T3 clones in which α-PDGFR signaling is inhibited by a dominant-negative α-PDGFR, or an antisense construct of α-PDGFR. Here, we demonstrate that β-PDGFR activation alone is sufficient for PDGF BB-mediated anchorage-independent cell growth. More importantly, inhibition of α-PDGFR signaling enhanced PDGF BB-mediated phenotypic transformation, suggesting that α-PDGFR antagonizes β-PDGFR-induced transformation. While both α- and β-receptors effectively activate ERKs, α-PDGFR, but not β-PDGFR, activates stress-activated protein kinase-1/cJun NH2-terminal kinase-1 (JNK-1). Inhibition of JNK-1 activity using a dominant-negative JNK-1 mutant markedly enhanced PDGF BB-mediated anchorage-independent cell growth, demonstrating an antagonistic role for JNK-1 in PDGF-induced transformation. Consistently, overexpression of wild- type JNK-1 reduced PDGF BB-mediated transformation. Taken together, the present study showed that α- and β-PDGFRs differentially regulate Ras- mitogen-activated protein kinase pathways critical for regulation of cell transformation, and transformation suppressing activity of α-PDGFR involves JNK-1 activation.