Semaphorin

Plexins comprise a family of transmembrane proteins that serve as receptors for semaphorins. On the basis... 

Both plexins and semaphorins are structurally characterized by the presence of an extracellular sema domain which contains a seven-blade 3-propeller. The... 

Plexins. Table 1 Plexins and their respective semaphorin ligands... 

Semaphorins and plexins were first described to be involved in the guidance of axonal growth cones during... 

The semaphorin-plexin system has been shown to be involved both in tumour suppression and tumour progression. The genes encoding Sema3B and Sema3F... 

Fiore R, Puschel AW (2003) The function of semaphorins during nervous system development. Front Biosci 8 s484-s499... 

Kruger RP, Aurandt J, Guan KL (2005) Semaphorins command cells to move. Nat Rev Mol Cell Biol 6 789-800... 

Neufeld G, Shraga-Heled N, Lange T et al (2005) Semaphorins in cancer. Front Biosci 10 751-760... 

Takegahara N, Kumanogoh A, Kikutani H (2005) Semaphorins a new class of immunoregulatory molecules. Philos Trans R Soc Lond B Biol Sci 360 1673-1680... 

The Sema domain consisting of about 500 amino acids is characterized by highly conserved cysteine residues that form intramolecular disulfide bonds. Crystal structures have revealed that the Sema domain folds in the manner of the (3 propeller topology which is also found in integrins or the low-density lipoprotein (LDL) receptors. Sema domains are found in semaphorins, plexins and in the receptor tyrosine kinases Met and Ron. 

Semaphorins are secreted, membrane-associated or transmembrane proteins defined by the presence of a sema-phorin protein domain (Serna domain). In the mammalian system, more than 20 semaphorins have been identified which play important roles in a variety of tissues. The best characterized receptors for mediating semaphoiin effects are members of the neuropilin and plexin families of transmembrane proteins. Semaphoiin functions are best described in the regulation of neural development, angiogenesis, immunoregulation and cancer. 

Neuropilin-1 (NRP1), a molecule that had been previously shown to be implicated in axon guidance as a receptor for members of collapsin/semaphorin family, has been characterized as a which interacts with the heparin-binding VEGF isoforms. 

These recognition molecules can either repel or attract growing axons, sending directions for axonal travel like a semaphore signaling a navy ship (Fig. 1 — 19). Indeed, some of these molecules are called semaphorins to reflect this function. Once the axon growth tip reaches port, it is told to collapse by semaphorin molecules called collapsins, allowing the axon to dock into its appropriate postsynaptic slip... 

Subsequent studies have identified Rndl (Oinuma et al, 2003), another member of the Rho GTPase subfamily, and the ErbB-2 tyrosine kinase (Swiercz et al, 2004) in the regulation of RhoA by plexins. Additionally, an apparent requirement for interaction of plexin B with RhoGEFs for potentiation of angiogenesis by semaphorins (Basile et al., 2004) and activation of MAPK pathways (Aurandt et al, 2006) by plexin Bl was identified. Yet, direct evidence for the mechanism by which plexins achieve this activation of RhoA has been elusive. A simple mechanism would be localization of the RhoGEF to membranes on stimulation of the pathway as discussed in Section III.B. Evidence for this comes from a study (Oinuma et al, 2003) with Rndl, which can bind directly to plexin Bl. 

Identification of ErbB-2 tyrosine kinase in plexin B1 signaling suggests a potential role for phosphorylation (Swiercz et al., 2004). Semaphorin 4D stimulates phosphorylation of both the kinase and plexin Bl. This raises the interesting possibility that the PDZ-RhoGEFs could also be targets of the kinase and that phosphorylation would facilitate their activation as discussed in the previous section. The activation mechanism remains to be determined but could also include tonic stimulation by the G12- or G13 proteins. 

Aurandt, J., Vikis, H. G., Gutkind, J. S., Ahn, N., and Guan, K. L. (2002). The semaphorin receptor plexin-Bl signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG. Proc. Natl. Acad. Sci. USA 99, 12085-12090. 

Basile, J. R., Barac, A., Zhu, T., Guan, K. L., and Gutkind, J. S. (2004). Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res. 64, 5212-5224. 

---