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The Journal of Neuroscience, December 1, 2004, 24(48):10826-10834; doi:10.1523/JNEUROSCI.3715-04.2004

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Cellular/Molecular
Mapping Netrin Receptor Binding Reveals Domains of Unc5 Regulating Its Tyrosine Phosphorylation

Robert P. Kruger,^1,2 Jeeyong Lee,^1,3 Weiquan Li,¹ and Kun-Liang Guan^1,3,4

¹Life Sciences Institute, ²Neuroscience Program, ³Department of Biological Chemistry, and ⁴Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109

Netrin and its receptors Unc5 and deleted in colorectal carcinoma (DCC) regulate axon guidance and cell migration. We defined domains involved in the interactions between netrin-1, DCC, and Unc5c. We show that Unc5 requires both Ig domains to interact with netrin. DCC binds through the fourth fibronectin type III domain, whereas netrin binds through multiple domains to both receptors. We examined the functional consequences of removing the netrin binding and nonbinding domains from Unc5 in vitro and in vivo. In human embryonic kidney 293 cells, removal of the netrin binding second Ig domain causes an increase in basal tyrosine phosphorylation, whereas removal of the netrin nonbinding thrombospondin domains decreases tyrosine phosphorylation. Moreover, experiments in Caenorhabditis elegans indicate that both netrin binding and nonbinding domains are necessary for phenotypic rescue of an unc-5 loss of function mutation.

Key words: DCC; Unc5; netrin; axon guidance; receptor phosphorylation; cell migration

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Received May 12, 2004; revised October 15, 2004; accepted October 18, 2004.

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