Semaphorin signaling in vascular and tumor biology.

The neuropilins were originally characterized as cell membrane receptors that bind axon guidance factors belonging to the class-3 semaphorin subfamily. To transduce semaphorin signals, they form complexes with members of the plexin receptor family in which neuropilins serve as the ligand binding components and the plexins as the signal transducing components. The neuropilins were subsequently found to double as receptors for specific heparin binding splice forms of vascular endothelial growth factor (VEGF), and to be expressed on endothelial cells.

The neuropilins and their role in tumorigenesis and tumor progression.

The neuropilins were originally described as receptors for the six axon guidance factors belonging to the class-3 semaphorins. They were subsequently found to function in addition as receptors for specific splice forms of angiogenic factors belonging to the VEGF family. The neuropilins are expressed in many types of cancer cells, in endothelial cells and in additional many types of normal diploid cell types.

Semaphorins in cancer.

The semaphorins are the products of a large family of genes currently containing more than 30 members. These genes are divided into eight classes of which classes 1, 2 and 8 contain invertebrate and viral semaphorins, while classes 3-7 contain the vertebrate semaphorins. The semaphorins have been implicated in diverse developmental processes such as axon guidance during nervous system development and regulation of cell migration.

Semaphorin-3F is an inhibitor of tumor angiogenesis.

The neuropilin-1 (np1) and neuropilin-2 (np2) receptors form complexes with type-A plexins. These complexes serve as signaling receptors for specific class-3 semaphorins. Np1 and np2 function in addition as receptors for heparin-binding forms of vascular endothelial growth factor (VEGF), such as VEGF(165).

VEGF162, a new heparin-binding vascular endothelial growth factor splice form that is expressed in transformed human cells.

The splice forms of vascular endothelial growth factor (VEGF) differ in biological properties such as the receptor types that they recognize and their interaction with heparan sulfate proteoglycans. We have identified a new VEGF mRNA splice form encoding a VEGF species containing 162 amino acids (VEGF(162)) in human A431 ovarian carcinoma cells. This novel mRNA contains the peptides encoded by exons 1-5, 6A, 6B, and 8 of the VEGF gene.

The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis.

The neuropilin-1 (np1) and neuropilin-2 (np2) receptors function as receptors for the axon guidance factors belonging to the class-3 semaphorin subfamily. In addition, both neuropilins are able to bind to certain heparin-binding splice forms of vascular endothelial growth factor (VEGF), indicating that both neuropilins have roles in the cardiovascular system as well. Gene targeting experiments indicate that np1 does indeed function as an important modulator of VEGF function during vasculogenesis and angiogenesis, but the role of np2 in the cardiovascular system has not been studied in detail as yet.