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First published online December 21, 2005
doi: 10.1242/10.1242/jcs.02697

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FAK and Src kinases are required for netrin-induced tyrosine phosphorylation of UNC5

¹ Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
² Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
³ Department of Neurobiology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
⁴ Institute of Gerontology, University of Michigan, Ann Arbor, MI 48109, USA

^* Authors for correspondence (e-mail: wqli{at}umich.edu; kunliang{at}umich.edu)

Accepted 16 September 2005

During neuronal development, netrin and its receptors UNC5 and DCC (deleted in colorectal cancer) guide axonal growth cones in navigating to their targets. Netrin also plays important roles in the regulation of cell migration, tissue morphogenesis and tumor growth. Here, we show that netrin induces UNC5 tyrosine phosphorylation and that this effect of netrin is dependent on its co-receptor DCC. UNC5 tyrosine phosphorylation is known to be important for netrin to induce cell migration and axonal repulsion. Src tyrosine kinase activity is required for netrin to stimulate UNC5 tyrosine phosphorylation in neurons and transfected cells. The SH2 domain of Src kinase directly interacts with the cytosolic domain of UNC5 in a tyrosine-phosphorylation-dependent manner. Furthermore, the tyrosine kinase focal adhesion kinase (FAK) is also involved in netrin-induced UNC5 tyrosine phosphorylation. Both Src and FAK can phosphorylate UNC5. Our data suggest a model in which netrin stimulates UNC5 tyrosine phosphorylation and signaling in a manner dependent on the co-receptor DCC, through the recruitment of Src and FAK kinases.

Key words: Src family tyrosine kinases, Focal adhesion kinase, FAK, Deleted in colorectal cancer, DCC, UNC5 receptor, Netrin signaling, Tyrosine phosphorylation