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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{triangledown}

Michael Maceyka,1,{dagger} Sergio E. Alvarez,1,{dagger} Sheldon Milstien,2 and Sarah Spiegel1*

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.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, VCU School of Medicine, P.O. Box 980614, 1101 E. Marshall St., Richmond, VA 23298-0614. Phone: (804) 828-9330. Fax: (804) 828-8999. E-mail: sspiegel{at}vcu.edu

{triangledown} Published ahead of print on 21 July 2008.

{dagger} These authors contributed equally.

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.



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