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Filamin A Links Sphingosine Kinase 1 And Sphingosine-1-Phosphate Receptor 1 At Lamellipodia To Orchestrate Cell Migration

Michael Maceyka, Sergio E. Alvarez, Sheldon Milstien, Sarah Spiegel

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ABSTRACT 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 S1P 1 (promotility S1P receptor) but not S1P 2 , with SphK1 and FLNa at membrane ruffles. Moreover, an S1P 1 antagonist inhibited the lamellipodia formation induced by heregulin. Hence, FLNa links SphK1 and S1P 1 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.