Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor

The netrins, a family of laminin-related secreted proteins, are critical in controlling axon elongation and pathfinding(1-4). The DCC (for deleted in colorectal cancer) protein was proposed as a receptor for netrin-1 in the l ight of many observations including the inhibition of netrin-1-mediated axo n outgrowth and attraction in the presence of an anti-DCC antiserum(5-7), t he similitude of nervous system defects in DCC and netrin-1 knockout mice(4 ,8) and the results of receptor swapping experiments(9). Previous studies h ave failed to show a direct interaction of DCC with netrin-1 (ref. 10), sug gesting the possibility of an additional receptor or coreceptor. Here we sh ow that DCC interacts with the membrane-associated adenosine A2b receptor, a G-protein-coupled receptor that induces cAMP accumulation on binding aden osine(11). We show that A2b is actually a netrin-1 receptor and induces cAM P accumulation on binding netrin-1. Finally, we show that netrin-1-dependen t outgrowth of dorsal spinal cord axons directly involves A2b. Together our results indicate that the growth-promoting function of netrin-1 may requir e a receptor complex containing DCC and A2b.