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Molecular and Cellular Biology, September 2008, p. 5687-5697, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00465-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Filamin A Links Sphingosine Kinase 1 and Sphingosine-1-Phosphate Receptor 1 at Lamellipodia To Orchestrate Cell Migration

Michael Maceyka,^1, Sergio E. Alvarez,^1, Sheldon Milstien,² and Sarah Spiegel^1*

Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298,¹ NIMH Intramural Research Program, NIH, Bethesda, Maryland 20892²

Received 20 March 2008/ Returned for modification 25 April 2008/ Accepted 9 July 2008

Sphingosine kinase 1 (SphK1) catalyzes the phosphorylation of sphingosine to produce the potent lipid mediator sphingosine-1-phosphate (S1P), which plays a critical role in cell motility via its cell surface receptors. Here, we have identified filamin A (FLNa), an actin-cross-linking protein involved in cell movement, as a bona fide SphK1-interacting protein. Heregulin stimulated SphK1 activity only in FLNa-expressing A7 melanoma cells but not in FLNa-deficient cells and induced its translocation and colocalization with FLNa at lamellipodia. SphK1 was required for heregulin-induced migration, lamellipodia formation, activation of PAK1, and subsequent FLNa phosphorylation. S1P directly stimulated PAK1 kinase, suggesting that it may be a target of intracellularly generated S1P. Heregulin also induced colocalization of S1P₁ (promotility S1P receptor) but not S1P₂, with SphK1 and FLNa at membrane ruffles. Moreover, an S1P₁ antagonist inhibited the lamellipodia formation induced by heregulin. Hence, FLNa links SphK1 and S1P₁ to locally influence the dynamics of actin cytoskeletal structures by orchestrating the concerted actions of the triumvirate of SphK1, FLNa, and PAK1, each of which requires and/or regulates the actions of the others, at lamellipodia to promote cell movement.

Published ahead of print on 21 July 2008.

These authors contributed equally.