The netrins, a family of laminin-related secreted proteins, are critical in controlling axon elongation and pathfinding1,2,3,4. The DCC (for deleted in colorectal cancer) protein was proposed as a receptor for netrin-1 in the light of many observations including the inhibition of netrin-1-mediated axon outgrowth and attraction in the presence of an anti-DCC antiserum5,6,7, the similitude of nervous system defects in DCC and netrin-1 knockout mice4,8 and the results of receptor swapping experiments9. Previous studies have failed to show a direct interaction of DCC with netrin-1 (ref. 10), suggesting the possibility of an additional receptor or co-receptor. Here we show that DCC interacts with the membrane-associated adenosine A2b receptor, a G-protein-coupled receptor that induces cAMP accumulation on binding adenosine11. We show that A2b is actually a netrin-1 receptor and induces cAMP accumulation on binding netrin-1. Finally, we show that netrin-1-dependent outgrowth of dorsal spinal cord axons directly involves A2b. Together our results indicate that the growth-promoting function of netrin-1 may require a receptor complex containing DCC and A2b.
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We thank L. Granger for technical assistance, P. Schofield for the human A2b expressing construct, and M. Tessier-Lavigne for the purified netrin-1. This work was supported by the CNRS, the Ligue Contre le Cancer, the FRM, the ARC (to P.M. and to A.C.), the ‘emmergence’ program (to P.M.), and APEX INSERM (to A.C.). K.T.N.-B.-C is a recipient of a postdoctoral fellowship from IRP.
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