Goparaju Sravan K, Jolly Puneet S, Watterson Kenneth R, Bektas Meryem, Alvarez Sergio, Sarkar Sukumar, Mel Lin, Ishii Isao, Chun Jerold, Milstien Sheldon, Spiegel Sarah
Department of Biochemistry, Virginia Commonwealth University Medical Center, 1101 E. Marshall Street, Room 2-011, Sanger Hall, Richmond, VA 23298-0614, USA.
Mol Cell Biol. 2005 May;25(10):4237-49. doi: 10.1128/MCB.25.10.4237-4249.2005.
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.
1-磷酸鞘氨醇（S1P）是一种具有生物活性的鞘脂代谢产物，是五种特定G蛋白偶联受体（命名为S1P(1)至S1P(5)）的配体。在本研究中，我们发现血小板衍生生长因子受体与S1P(2)之间的交叉通讯作为PDGF功能的负调节因子。删除S1P(2)受体会显著增加小鼠胚胎成纤维细胞向S1P、血清和PDGF的迁移，但对纤连蛋白无此作用。这种增强的迁移依赖于S1P(1)和鞘氨醇激酶1（SphK1，产生S1P的酶）的表达，分别通过反义RNA和小干扰RNA下调它们的表达得以揭示。尽管删除S1P(2)对PDGF受体的酪氨酸磷酸化或PDGF诱导的细胞外信号调节激酶1/2或Akt的激活没有显著影响，但它减少了持续的PDGF依赖性p38磷酸化并显著增强了Rac激活。令人惊讶的是，缺乏S1P(2)的细胞不仅表现出增殖增强，而且SphK1的表达和活性也显著增加。相反，重新引入S1P(2)会减少DNA合成和SphK1的表达。因此，S1P(2)作为PDGF诱导的迁移、增殖以及SphK1表达的负调节因子。我们的结果表明，PDGFR和S1P受体之间复杂的相互作用决定了它们的功能。
