Abstract
Semaphorins are the products of a large gene family containing 28 genes of which 21 are found in vertebrates. Class-3 semaphorins constitute a subfamily of seven vertebrate semaphorins which differ from the other vertebrate semaphorins in that they are the only secreted semaphorins and are distinguished from other semaphorins by the presence of a basic domain at their C termini. Class-3 semaphorins were initially characterized as axon guidance factors, but have subsequently been found to regulate immune responses, angiogenesis, lymphangiogenesis, and a variety of additional physiological and developmental functions. Most class-3 semaphorins transduce their signals by binding to receptors belonging to the neuropilin family which subsequently associate with receptors of the plexin family to form functional class-3 semaphorin receptors. Recent evidence suggests that class-3 semaphorins also fulfill important regulatory roles in multiple forms of cancer. Several class-3 semaphorins function as endogenous inhibitors of tumor angiogenesis. Others were found to inhibit tumor metastasis by inhibition of tumor lymphangiogenesis, by direct effects on the behavior of tumor cells, or by modulation of immune responses. Notably, some semaphorins such as sema3C and sema3E have also been found to potentiate tumor progression using various mechanisms. This review focuses on the roles of the different class-3 semaphorins in tumor progression.
Highlights
Semaphorins are the products of a large gene family containing 28 genes of which 21 are found in vertebrates
Unlike similar cleavage products derived from sema3A or sema3B which lack bioactivity or display strongly reduced activity, p61-Sema3E retains the activity of full-length sema3E, but unlike full length sema3E, able induces the formation of complexes between plexin-D1 and the ErbB2 tyrosine-kinase receptor resulting in the in-trans activation of ErbB2 signal transduction, which in turn promotes tumor metastasis [14]
The class-3 semaphorins were initially found to function as axon guidance factors but were recently found to affect a much wider range of biological processes including angiogenesis, lymphangiogenesis and immune surveillance and to be players in the etiology of many diseases including cancer
Summary
Class-3 semaphorins (sema3A-3G) are characterized, like all semaphorins, by the presence of a ~500 amino-acid-long sema domain located close to their N-termini which is present in semaphorin receptors of the plexin family. Like all semaphorins, they contain a plexin-semaphorin-integrin (PSI) domain located downstream to the sema domain. The intracellular domain of neuropilin-1 contains a PDZ binding domain which binds synectin ( known as GIPC or NIP) and this interaction is important for the formation of complexes with VEGFR-2 [52,53]
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