Transmembrane semaphorins: Multimodal signaling cues in development and cancer

Abstract

Semaphorins constitute a large family of membrane-bound and secreted proteins that provide guidance cues for axon pathfinding and cell migration. Although initially discovered as repelling cues for axons in nervous system, they have been found to regulate cell adhesion and motility, angiogenesis, immune function and tumor progression. Notably, semaphorins are bifunctional cues and for instance can mediate both repulsive and attractive functions in different contexts. While many studies focused so far on the function of secreted family members, class 1 semaphorins in invertebrates and class 4, 5 and 6 in vertebrate species comprise around 14 transmembrane semaphorin molecules with emerging functional relevance. These can signal in juxtacrine, paracrine and autocrine fashion, hence mediating long and short range repulsive and attractive guidance cues which have a profound impact on cellular morphology and functions. Importantly, transmembrane semaphorins are capable of bidirectional signaling, acting both in "forward" mode via plexins (sometimes in association with receptor tyrosine kinases), and in "reverse" manner through their cytoplasmic domains. In this review, we will survey known molecular mechanisms underlying the functions of transmembrane semaphorins in development and cancer.

Keywords: cancer; development; plexins; semaphorins; signaling mechanisms.

Figure 1.

Representative transmembrane semaphorins and their receptor complexes. A number of transmembrane semaphorins signal through diverse receptor complexes. Notable examples are illustrated in this figure. Sema4A can bind to Tim-2, a protein expressed on T cells, in addition to plexins. In lymphocytes, Sema4D can associate with CD72, a member of the C-type lectin family. In cancer cells, Sema4D can signal through complexes including PlexinB1 and ErbB2 or Met depending on the cell type. Sema5A can signal through PlexinB3 and Met in epithelial cancer cells. However, in neurons, proteoglycans such as HSPG and CSPG modulate Sema5A signaling, independent of PlexinB3. PlexinA1 is alternatively associated with OTK or VEGFR2 receptor tyrosine kinases in different cells of the developing heart, and these signaling complexes have distinct functions in cardiac development.

Figure 2.

Various signaling mode paradigms used by Sema4D transmembrane semaphorin. Sema4D is taken as an example of diverse signaling paradigms of transmembrane semaphorins. In particular, Sema4D produced by endothelial cells can function in autocrine manner on its surface receptor such a PlexinB1. In addition, Sema4D released by other cells in the tumor microenvironment (e.g., Tumor Associated Macrophages) can signal in paracrine fashion to endothelial cells. Moreover, during wound healing, Sema4D expressed by dendritic epidermal T cells can bind to PlexinB2 expressed on the surface of damaged keratinocytes, acting in juxtacrine mode.

Figure 3.

Forward and reverse signaling effectors of transmembrane semaphorins. The general paradigm of forward and reverse signaling of transmembrane semaphorins is depicted on the left. On the right, a table summarizes various effectors implicated in these distinctive signaling modes for different family members.