Differential interferences of the pdgf receptor signaling pathways by tgf- βi in mg-63 human osteosarcoma cells

PDGF elicits its effect by binding to specific cell surface receptors leading to autophosphorylation of the receptor molecules on specific tyrosine residues. Tyrosine phosphorylation of the receptors increase the recruitment of several SH2 domain-containing signaling molecules resulting in the enhancement of their activities. TGF-/? has been shown to suppress the growth promoting effect of several mitogens, including PDGF, in a number of cell systems. Although it has been clear that TGF- /?R is a serine/threonine kinase, however, as how TGF-/? suppresses the mitogenic signaling of tyrosine kinase receptor pathways has not been fully elucidated. We previously found that TGF- βinhibited PDGF mitogenicity in MG-63 cells and such inhibition was correlated with a suppression of PDGF-induced receptor autophosphorylation. In this study, we analyze if all the PDGFR signaling pathways are similarly affected by the TGF-/? pretreatment. We show that TGF- βsuppresses PDGF stimulated tyrosine phosphorylation of PLC T l and Erk, however, the tyrosine phosphorylation of PI3-kinase is not affected. Thus, TGF- βselectively suppresses two out of three PDGFR signaling pathways despite of its prominent inhibition of the PDGF-induced PDGFR autophosphorylation.