Shedding Light on the Proteolytically Released Ectodomains of Membrane-Bound Semaphorins

Semaphorins (Semas) are secreted and membrane-bound molecules classically characterized as axonal guidance cues in nervous system development. However, it is now widely appreciated that Semas have essential functions in the development of many systems including the cardiovascular, endothelial, and immune systems. Secreted Semas enable functionality distant from the site of release, while membrane-bound Semas mediate localized contact-dependent signaling. Interestingly, functional soluble ectodomains have been discovered in each of the four vertebrate membrane-bound classes which can drive change in the nature and reach of Sema signaling. This review highlights the discovery of these soluble Sema ectodomains, the mechanisms of their release, and their known roles in development and pathological states.