Class-3 Semaphorins and Their Receptors: Potent Multifunctional Modulators of Tumor Progression

Abstract

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.

Keywords: angiogenesis; cancer; lymphangiogenesis; neuropilins; plexins; semaphorins.

Figure 1

The vertebrate semaphorins: Shown are the main structural features of the sub-families of the vertebrate semaphorins. The 21 members of the vertebrate semaphorin family all contain the hallmark sema domain and are divided into five subfamilies based upon structural features. The seven class-3 semaphorins are the only secreted semaphorins and are also distinguished from the other semaphorins by their basic c-terminal domain.

Figure 2

The class-3 semaphorins and their receptors: The compositions of the functional receptor complexes that transduce the signals of the different class-3 semaphorins to induce cytoskeletal collapse in different cell types are shown. Plex stands as an abbreviation for plexin and Np as an abbreviation for neuropilins. Shown also are the main structural elements of the different plexins and neuropilins that function as class-3 semaphorin receptors. Neuropilins and plexins are single-pass transmembrane receptors. Neuropilins contain two complement-like binding domains (CUB domains also known as the a1 and a2 domains) that bind class 3 semaphorins. They contain two FV/FVIII coagulation factor homology domains (also termed the b1 and b2 domains). The b1 domain also participates in the binding of class-3 semaphorins. In contrast, VEGF binds to both. The MAM domain is believed to mediate neuropilin dimerization. The intracellular domain of the neuropilins contains a C-terminal SEA sequence that interacts with the PDZ domain containing proteins such as synectin. Plexins also contain a sema domain in their extracellular domain. They contain PSI (Plexin, Semaphorin, Integrin) motifs and IPT/(G-P)-rich motifs involved in the binding of semaphorins. The intracellular part contains a split GTPase activating (GAP) domain separated by a GTPase-binding domain that binds small GTPases such as Rac.

Figure 3

Sema3A inhibits VEGFR-2-mediated pro-angiogenic signaling by activation of an inhibitory intracellular signaling cascade: Sema3A binds to its neuropilin-1 receptor, thereby activating type-A plexins. This inhibits VEGF-A-induced phosphorylation of extracellular signal–regulated kinase-1/2 (ERK-1/2). However, sema3A does not compete with VEGF-A for binding to neuropilin-1 since the binding sites are completely separate. Indeed, sema3A does not inhibit VEGF-A-induced auto-phosphorylation of VEGFR-2 suggesting independently that the inhibition does not take place at the level of the VEGF-A receptors.