Semaphorins mediate axon repulsion through interactions with their receptors the Plexins. Two papers now identify some of the signaling elements in axon guidance that are mediated by Plexin A and Plexin B: Hu et al. investigated signaling from Plexin B to two cytoskeletal regulators, the Rac and Rho guanosine triphosphatases (GTPases). Winberg et al. show that Off-track (OTK, formerly known as Dtrk, which has similarity to receptor tyrosine kinases, but lacks catalytic activity) functions in Plexin A signaling. Hu et al. show that Drosophila Plexin B interacts with both Rac and RhoA small GTPases, although these interactions occur on different regions of Plexin B. Genetic interactions between Rac and Plexin B indicate that Plexin B decreases Rac activity, whereas genetic interactions between RhoA and Plexin B indicate that Plexin B stimulates RhoA. Biochemical experiments using glutathione-S-transferase fusion proteins showed that Plexin B competed with p21-activating kinase (PAK) for binding to the activated, GTP-bound form of Rac, suggesting that the mechanism of down-regulation might be through sequestration of the active form of Rac. Plexin B appears to mediate its effects by activating one class of GTPases and sequestering another, thus altering the balance of cytoskeletal regulation in favor of neurite retraction. Switching to Plexin A signaling, Winberg et al. determined that OTK could be immunoprecipitated with Plexin A from mammals and Drosophila when these proteins were expressed together in transfected cells, suggesting that they form a complex. Drosophila with loss-of-function mutations in OTK have phenotypes similar to those with Plexin A and Sema 1a loss-of-function mutants. Furthermore, genetic interactions place OTK downstream of Sema 1a. Thus, OTK appears to be part of the Sema 1a signaling pathway; however, it is unlikely that OTK is the tyrosine kinase that results in Plexin A and OTK tyrosine phosphorylation. Although OTK has some similarities to receptor tyrosine kinases (a single transmembrane domain and an intracellular region with sequence similarity to tyrosine kinases), OTK lacks essential amino acids necessary for catalytic activity. Thus, exactly how OTK is involved in Semaphorin signaling remains a mystery. These two papers are discussed by Whitford and Ghosh.
H. Hu, T. F. Marton, C. S. Goodman, Plexin B mediates axon guidance in Drosophila by simultaneously inhibiting active Rac and enhancing RhoA signaling. Neuron 32, 39-51 (2001). [Online Journal]
M. L. Winberg, L. Tamagnone, J. Bai, P. M. Comoglio, D. Montell, C. S. Goodman, The transmembrane protein Off-track associates with plexins and functions downstream of semaphorin signaling during axon guidance. Neuron 32, 53-62 (2001). [Online Journal]
K. L. Whitford, A. Ghosh, Plexin signaling via Off-track and Rho family GTPases. Neuron 32, 1-8 (2001). [Online Journal]