V. Corset et al., Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor, NATURE, 407(6805), 2000, pp. 747-750
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.