Sphingosine kinase 1 is a critical component of the copper-dependent FGF1 export pathway.
Sphingosine kinase 1 catalyzes the formation of sphingosine-1-phosphate, a lipid mediator involved in the regulation of angiogenesis. Sphingosine kinase 1 is constitutively released from cells, even though it lacks a classical signal peptide sequence. Because copper-dependent non-classical stress-induced release of FGF1 also regulates angiogenesis, we questioned whether sphingosine kinase 1 is involved in the FGF1 release pathway. We report that (i) the coexpression of sphingosine kinase 1 with FGF1 inhibited the release of sphingosine kinase 1 at 37 degrees C; (ii) sphingosine kinase 1 was released at 42 degrees C in complex with FGF1; (iii) sphingosine kinase 1 null cells failed to release FGF1 at stress; (iv) sphingosine kinase 1 is a high affinity copper-binding protein which formed a complex with FGF1 in a cell-free system, and (v) sphingosine kinase 1 over expression rescued the release of FGF1 from inhibition by the copper chelator, tetrathiomolybdate. We propose that sphingosine kinase 1 is a component of the copper-dependent FGF1 release pathway.
Soldi
Raffaella
R
Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA.
Mandinova
Anna
A
Venkataraman
Krishnan
K
Hla
Timoty
T
Vadas
Mathew
M
Pitson
Stuart
S
Duarte
Maria
M
Graziani
Irene
I
Kolev
Vihren
V
Kacer
Doreen
D
Kirov
Aleksandr
A
Maciag
Thomas
T
Prudovsky
Igor
I
D000818:Animals; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003001:Cloning, Molecular; D003300:Copper / Q000378:metabolism*; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008982:Molybdenum / Q000494:pharmacology; D041681:NIH 3T3 Cells; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D013696:Temperature; D000099157:Sphingosine Kinase
D002614:Chelating Agents; D003300:Copper; D016220:Fibroblast Growth Factor 1; D008982:Molybdenum; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase; C020809:tetrathiomolybdate