Semaphorin-3E (Sema3E) is a secreted glycoprotein that has risen to prominence because of its widespread and often critical role as a signaling molecule in processes as diverse as axon guidance, angiogenesis, immune regulation, and cancer. Sema3E signals through the cell surface receptor plexin-D1, and in a capacity unique among class 3 semaphorins, Sema3E activates its receptor complex without requiring the presence of a neuropilin co-receptor. Sema3E was initially discovered in mice where its two major roles were quickly identified: as a key protein in directing axon growth during development, and as a negative regulator in cancer, where it was found to intensify cancer metastases. During development, Sema3E/plexin-D1 functions to guide a regulated and directed pattern of vascular, somite, and neuronal growth in the developing embryo. Beyond development, Sema3E has been implicated in several disease states including inflammatory and vascular diseases, but most notably cancer. In cancer, Sema3E has been found to act directly on cancer cells by promoting cancer cell proliferation and metastasis; however, it has also been shown to have anti-angiogenic and tumor suppressor effects on some cancers. The discovery that furin-mediated cleavage of Sema3E could convert the protein into a pro-metastatic factor has now become a focal point of research on the molecule and likely explains the disparate observations of Sema3E’s effects in cancer. The evidence is clear that Sema3E plays an important role in cancer, but a deeper understanding of the precise functions of the protein in different contexts and conditions is still required before Sema3E can be used as a therapeutic target or prognostic marker for the disease.
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