The S1P2 receptor negatively regulates platelet-derived growth factor-induced motility and proliferation

Sphingosine-1-phosphate (SIP), a bioactive sphingolipid metabolite, is the ligand for five specific G protein-coupled receptors, named SIP, to SIP,. In this study, we found that cross-communication between platelet-derived growth factor receptor and SIP, serves as a negative damper of PDGF functions. Deletion of the S1P(2) receptor dramatically increased migration of mouse embryonic fibroblasts toward SIP, serum, and PDGF but not fibronectin. This enhanced migration was dependent on expression of SIP, and sphingosine kinase 1 (SphK1), the enzyme that produces SIP, as revealed by downregulation of their expression with antisense RNA and small interfering RNA, respectively. Although S1P(2) 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, S1P(2)-null cells not only exhibited enhanced proliferation but also markedly increased SphK1 expression and activity. Conversely, reintroduction of S1P(2) reduced DNA synthesis and expression of SphK1. Thus, S1P(2) serves as a negative regulator of PDGF-induced migration and proliferation as well as SphKI expression. Our results suggest that a complex interplay between PDGFR and SIP receptors determines their functions.