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Article
Nature Neuroscience  7, 1213 - 1221 (2004)
Published online: 17 October 2004; | doi:10.1038/nn1329

Activation of FAK and Src are receptor-proximal events required for netrin signaling

Weiquan Li1, Jeeyong Lee1, 2, Haris G Vikis2, Seung-Hee Lee3, Guofa Liu4, Jennifer Aurandt1, 2, Tang-Long Shen5, Eric R Fearon6, Jun-Lin Guan5, Min Han7, Yi Rao4, Kyonsoo Hong3 & Kun-Liang Guan1, 2, 8

1  Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.

2  Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.

3  Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.

4  Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

5  Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.

6  Departments of Human Genetics and Internal Medicine and Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.

7  Department of Molecular Cellular Developmental Biology, Howard Hughes Medical Institute, University of Colorado, Boulder, Colorado 80309, USA.

8  Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109, USA.

Correspondence should be addressed to Kun-Liang Guan kunliang@umich.edu
The axon guidance cue netrin is importantly involved in neuronal development. DCC (deleted in colorectal cancer) is a functional receptor for netrin and mediates axon outgrowth and the steering response. Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.

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Nature Neuroscience
ISSN: 1097-6256
EISSN: 1546-1726
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