The S1P2 receptor negatively regulates platelet-derived growth factor-induced motility and proliferation.
Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, is the ligand for five specific G protein-coupled receptors, named S1P(1) to S1P(5). In this study, we found that cross-communication between platelet-derived growth factor receptor and S1P(2) serves as a negative damper of PDGF functions. Deletion of the S1P(2) receptor dramatically increased migration of mouse embryonic fibroblasts toward S1P, serum, and PDGF but not fibronectin. This enhanced migration was dependent on expression of S1P(1) 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 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 SphK1 expression. Our results suggest that a complex interplay between PDGFR and S1P receptors determines their functions.
Goparaju
Sravan K
SK
Department of Biochemistry, Virginia Commonwealth University Medical Center, 1101 E. Marshall Street, Room 2-011, Sanger Hall, Richmond, VA 23298-0614, USA.
Jolly
Puneet S
PS
Watterson
Kenneth R
KR
Bektas
Meryem
M
Alvarez
Sergio
S
Sarkar
Sukumar
S
Mel
Lin
L
Ishii
Isao
I
Chun
Jerold
J
Milstien
Sheldon
S
Spiegel
Sarah
S
D000818:Animals; D021961:Cell Membrane Structures / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D008297:Male; D051379:Mice; D008954:Models, Biological; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D000099157:Sphingosine Kinase
D017853:Phosphotransferases (Alcohol Group Acceptor); D010982:Platelet-Derived Growth Factor; D049349:Receptors, Lysosphingolipid; D020744:rac GTP-Binding Proteins; D000099157:Sphingosine Kinase