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

被引:108
作者
Gräler, MH
Grosse, R
Kusch, A
Kremmer, E
Gudermann, T
Lipp, M
机构
[1] Max Delbruck Ctr Mol Med, Dept Tumor Genet & Immunogenet, D-13092 Berlin, Germany
[2] Canc Res UK, Transcript Lab, London Res Inst, London WC2A 3PX, England
[3] GSF Munich, Natl Res Ctr Environm & Hlth, Inst Mol Immunol, D-81377 Munich, Germany
[4] Univ Marburg, Inst Pharmacol & Toxicol, D-35033 Marburg, Germany
关键词
sphingosine; 1-phosphate; endothelial differentiation gene; G protein-coupled receptor; lymphocyte; immune system;
D O I
10.1002/jcb.10537
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Sphingosine 1-phosphate (S1P) receptors represent a novel subfamily of G-protein-coupled receptors binding SIP specifically and with high affinity. Although their in vivo functions remain largely unknown, in vitro extracellular application of SIP induces distinct S1P receptor-dependent cellular responses including proliferation, differentiation, and migration. We have analyzed signaling pathways engaged by S1P(4), which is highly expressed in the lymphoid system. Here we show that S1P(4) couples directly to Galpha(i) and even more effectively to Galpha(12/13)-subunits of trimeric G-proteins, but not to Galpha(q) unlike other S1P receptors. Consequently, CHO-K1 cells ectopically expressing S1P(4) potently activate the small GTPase Rho and undergo cytoskeletal rearrangements, inducing peripheral stress fiber formation and cell rounding, upon S1P stimulation. Overexpression of S1P(4) in Jurkat T cells induces pertussis toxin-sensitive cell motility even in the absence of exogenously added S1P. In addition, S1P(4) is internalized upon binding of S1P. The capacity of S1P(4) to mediate cellular responses, such as motility and shape change through Goalpha(i)- and Galpha(12/13)-coupled signaling pathways may be important for its in vivo function which is currently under investigation.
引用
收藏
页码:507 / 519
页数:13
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