Semaphorins and their Signaling Mechanisms

Semaphorins are extracellular signaling proteins that are essential for the development and maintenance of many organs and tissues. The more than 20-member semaphorin protein family includes secreted, transmembrane and cell surface-attached proteins with diverse structures, each characterized by a single cysteine-rich extracellular sema domain, the defining feature of the family. Early studies revealed that semaphorins function as axon guidance molecules, but it is now understood that semaphorins are key regulators of morphology and motility in many different cell types including those that make up the nervous, cardiovascular, immune, endocrine, hepatic, renal, reproductive, respiratory and musculoskeletal systems, as well as in cancer cells. Semaphorin signaling occurs predominantly through Plexin receptors and results in changes to the cytoskeletal and adhesive machinery that regulate cellular morphology. While much remains to be learned about the mechanisms underlying the effects of semaphorins, exciting work has begun to reveal how semaphorin signaling is fine-tuned through different receptor complexes and other mechanisms to achieve specific outcomes in various cellular contexts and physiological systems. These and future studies will lead to a more complete understanding of semaphorin-mediated development and to a greater understanding of how these proteins function in human disease.