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Cell migration activated by platelet‐derived growth factor receptor is blocked by an inverse agonist of the sphingosine 1‐phosphate receptor‐1
Author(s) -
Waters Catherine M.,
Long Jaclyn,
Gorshkova Irina,
Fujiwara Yuko,
Connell Michelle,
Belmonte Kristen E.,
Tigyi Gabor,
Natarajan Viswanathan,
Pyne Susan,
Pyne Nigel J.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4810fje
Subject(s) - inverse agonist , sphingosine 1 phosphate receptor , sphingosine 1 phosphate , receptor , sphingosine , agonist , chemistry , microbiology and biotechnology , endocrinology , medicine , biochemistry , biology
We have previously identified a novel complex between the platelet‐derived growth factor (PDGF)? 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 PDGF? 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 PDGF? 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 receptor‐induced GTP?S binding and S1P‐induced GTP?S 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 PDGF? 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 PDGF‐induced cell migration.