Axonal guidance molecules guide the growth of neuronal axons to their targets during the development of the nervous system. The guidance molecule netrin has two receptors: DCC transduces attractive signals, whereas UNC5 (alone or together with DCC) transduces repulsive signals. The signalling pathways downstream of UNC5 and DCC are poorly understood. Now, Kun-Liang Guan and colleagues report that netrin stimulates tyrosine phosphorylation of UNC5 in a DCC-dependent manner, and this involves recruitment of focal adhesion kinase (FAK) and Src (see p. 47). The authors show that netrin induces UNC5 phosphorylation in cultured mouse neurons and that DCC stimulates this. Other experiments indicate that Src and FAK can each phosphorylate UNC5 in vitro but both tyrosine kinases are needed to stimulate UNC5 phosphorylation efficiently in vivo. The authors propose that activation of the DCC-UNC5 receptor complex by netrin causes the recruitment and activation of Src and FAK, which tyrosine phosphorylate UNC5 to create binding sites for the downstream signalling molecules that generate a repulsive signal in response to netrin.
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