Semaphorins are secreted or transmembrane proteins that regulate cell motility and attachment in axon guidance, vascular growth, immune cell regulation and tumour progression. The main receptors for semaphorins are plexins, which have established roles in regulating Rho-family GTPases. Recent work shows that plexins can also influence R-Ras, which, in turn, can regulate integrins. Such regulation is probably a common feature of semaphorin signalling and contributes substantially to our understanding of semaphorin biology.

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.During embryonic development, neurons are guided to specific targets by extracellular cues in their environment. Axon growth cones sense various chemoattractive and chemorepulsive signals and translate these signals, via intracellular signal transduction pathways, into cellular movements that ultimately steer them to their correct targets. Several axon guidance molecules have been discovered and characterized, including a soluble family of proteins called netrins 1-3 . Netrins can stimulate axon growth in addition to eliciting both attractive and repulsive responses 4 .Correspondence should be addressed to K.-L.G. (kunliang@umich.edu). Competing Interests Statement:The authors declare that they have no competing financial interests.Note: Supplementary information is available on the Nature Neuroscience website. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2008 May 6. Published in final edited form as:Nat Neurosci. 2004 November ; 7(11): 1213-1221. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGenetic studies in Caenorhabditis elegans indicate that UNC-40 and UNC-5 are functional receptors for UNC-6, a netrin homolog 5-7 . The mammalian homolog of UNC-40 is DCC, originally identified as a tumor suppressor gene 8 . DCC mediates both the axon growth and the chemoattractive function of netrin 6,7,9 . In addition, DCC mediates growth cone repulsion when in a complex with the UNC-5 receptor 5,10-13 . The UNC-40 and UNC-5 receptor complex is required for the dorsoventral repulsion of both neurons and gonads in C. elegans. The biological functions of netrin and its receptors in axon growth and growth cone guidance have been well studied; the intracellular signal transduction pathways downstream of the netrin receptors, however, are only partially understood.Tyrosine phosphorylation may be involved downstream of guidance receptors, as phosphorylation of both DCC and UNC-5 has been observed 14 . Furthermore, coexpression of Src, a tyrosine kinase, increases UNC-5 tyrosine phosphorylation, indicating a Results Netrin stimulates tyrosine phosphorylation of DCC and FAKIt has b...

No abstract