The sphingosine 1‐phosphate receptor S1P4 regulates cell shape and motility via coupling to Gi and G12/13

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Abstract
Sphingosine 1‐phosphate (S1P) receptors represent a novel subfamily of G‐protein‐coupled receptors binding S1P specifically and with high affinity. Although their in vivo functions remain largely unknown, in vitro extracellular application of S1P induces distinct S1P receptor‐dependent cellular responses including proliferation, differentiation, and migration. We have analyzed signaling pathways engaged by S1P4, which is highly expressed in the lymphoid system. Here we show that S1P4 couples directly to Gαi and even more effectively to Gα12/13‐subunits of trimeric G‐proteins, but not to Gαq unlike other S1P receptors. Consequently, CHO‐K1 cells ectopically expressing S1P4 potently activate the small GTPase Rho and undergo cytoskeletal rearrangements, inducing peripheral stress fiber formation and cell rounding, upon S1P stimulation. Overexpression of S1P4 in Jurkat T cells induces pertussis toxin‐sensitive cell motility even in the absence of exogenously added S1P. In addition, S1P4 is internalized upon binding of S1P. The capacity of S1P4 to mediate cellular responses, such as motility and shape change through Gαi‐ and Gα12/13‐coupled signaling pathways may be important for its in vivo function which is currently under investigation.