The S1P₂ Receptor Negatively Regulates Platelet-Derived Growth Factor-Induced Motility and Proliferation

Abstract

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, is the ligand for five specific G protein-coupled receptors, named S1P₁ to S1P₅. In this study, we found that cross-communication between platelet-derived growth factor receptor and S1P₂ serves as a negative damper of PDGF functions. Deletion of the S1P₂ receptor dramatically increased migration of mouse embryonic fibroblasts toward S1P, serum, and PDGF but not fibronectin. This enhanced migration was dependent on expression of S1P₁ and sphingosine kinase 1 (SphK1), the enzyme that produces S1P, as revealed by downregulation of their expression with antisense RNA and small interfering RNA, respectively. Although S1P₂ deletion had no significant effect on tyrosine phosphorylation of the PDGF receptors or activation of extracellular signal-regulated kinase 1/2 or Akt induced by PDGF, it reduced sustained PDGF-dependent p38 phosphorylation and markedly enhanced Rac activation. Surprisingly, S1P₂-null cells not only exhibited enhanced proliferation but also markedly increased SphK1 expression and activity. Conversely, reintroduction of S1P₂ reduced DNA synthesis and expression of SphK1. Thus, S1P₂ serves as a negative regulator of PDGF-induced migration and proliferation as well as SphK1 expression. Our results suggest that a complex interplay between PDGFR and S1P receptors determines their functions.

ACKNOWLEDGMENTS

This work was supported by National Institutes of Health grant CA61774 (to S.S.) and, in part, by MH01723 (to J.C.).