Semaphorins

Abstract The semaphorins are an evolutionary conserved family of intercellular signalling proteins known to deliver guidance cues to growing axons and migrating cells during development. Semaphorins bind with high affinity to several distinct receptor families on the cell surface, including the neuropilins and plexins. The interaction of semaphorins and their receptor complexes triggers elaborate intracellular signalling pathways that in many cases regulate the cytoskeleton to control growth cone or cellular morphology. However, semaphorins also regulate cellular processes not directly related to changes in cytoskeletal dynamics such as apoptosis or cytokine release. Defects in semaphorin function have been associated with a variety of human diseases including amyotrophic lateral sclerosis, spinal cord injury and cancer, and studies have been initiated to use semaphorin proteins as therapeutic targets in human disorders. Key Concepts: Semaphorins are bi‐functional guidance cues mediating attractive and repulsive chemotactic responses. Semaphorin receptor complexes are composed of ligand binding, signal‐transducing and modulatory subunits. Context‐dependent changes in receptor or signalling components determine the downstream effect of semaphorins. Semaphorins can act as ligands and receptors, a process called bi‐directional signalling. Secreted and membrane‐associated semaphorins regulate various aspects of neural circuit development. Signalling cues that function downstream of semaphorin receptors includes protein kinases and small GTPases. Semaphorins have been implicated in various human diseases and may serve as therapeutic targets.