Cell migration activated by platelet-derived growth factor receptor is blocked by an inverse agonist of the sphingosine 1-phosphate receptor-1

C. Waters, J.S.L. Long, I. Gorshkova, Y. Fujiwara, M. Connell, K.E. Belmonte, G. Tigyi, V. Natarajan, S. Pyne, N.J. Pyne

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

We have previously identified a novel complex between the platelet-derived growth factor (PDGF)β receptor and the sphingosine 1-phosphate receptor-1 (S1P1). The complex permits the utilization of active G-protein subunits (made available by constitutively active S1P1 receptor) by the PDGFβ receptor kinase to transmit signals to p42/p44 MAPK in response to PDGF. Therefore, an inverse agonist of the S1P1 receptor is predicted to reduce signal transduction from
PDGFβ receptor tyrosine kinase by blocking the constitutive activity of the G-protein coupled receptor. SB649146 is a novel inverse agonist of the S1P1 receptor. First, SB649146 displaced the S1P1 receptor agonist dihydrosphingosine 1-phosphate from membranes expressing the recombinant S1P1 receptor. Second, SB649146 reduced basal recombinant S1P1 eceptorinduced GTPγS binding and S1P-induced GTPγS binding in membranes. Third, SB649146 blocked the S1P-induced activation of p42/p44 MAPK in airway smooth muscle cells, a response that is mediated by the S1P1 receptor. We now report that inverse agonism of the S1P1 receptor with SB649146 reduced the endocytosis of the PDGFβ receptor-S1P1 receptor complex and the stimulation of p42/p44 MAPK and cell migration in response to PDGF. These findings are the
first to report that a GPCR inverse-agonist reduces growth factor-induced receptor tyrosine kinase signaling, fundamentally broadening their mechanism of action. The data obtained with SB649146 also suggest that the constitutively active endogenous S1P1 receptor enhances PDGFinduced cell migration.
Original languageEnglish
Pages (from-to)509-511
Number of pages3
JournalFASEB Journal
Volume20
DOIs
Publication statusPublished - 2006

Keywords

  • integrative signaling
  • PDGFβ receptor
  • p42/p44 mitogen-activated protein kinase (MAPK)
  • constitutive GPCR
  • receptor tyrosine kinase

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