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. 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 antiserum, the similitude of nervous system defects in DCC and netrin-1 knockout mice and the results of receptor swapping experiments. 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 adenosine. 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.
Corset
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Laboratoire Apoptose et Différenciation, label La Ligue-Centre de Génétique Moléculaire et Cellulaire, CNRS UMR 5534, Université Lyon 1, Villeurbanne, France.
Nguyen-Ba-Charvet
K T
KT
Forcet
C
C
Moyse
E
E
Chédotal
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A
Mehlen
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P
D000818:Animals; D001369:Axons / Q000502:physiology*; D001921:Brain / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D002645:Chickens; D046508:Culture Techniques; D000242:Cyclic AMP / Q000096:biosynthesis*; D000075389:DCC Receptor; D020439:Growth Cones; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D051381:Rats; D043704:Receptor, Adenosine A2B; D011956:Receptors, Cell Surface / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques
D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; C501909:DCC protein, human; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D043704:Receptor, Adenosine A2B; D011956:Receptors, Cell Surface; D018047:Receptors, Purinergic P1; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D000242:Cyclic AMP