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.

Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential

“…Semaphorins can elicit a so-called "forward" signaling cascade through the intracellular domain of receptors in the Plexin family, controlling integrin-mediated adhesion and cytoskeletal remodeling [3]. Moreover, transmembrane semaphorins can mediate "reverse" signaling cascades mediated by their own cytoplasmic domains [4].…”

Role of Semaphorin Signaling During Cardiovascular Development

“…SEMA1A/Fasciclin IV is the founding member of the semaphorin family and was first reported in 1992 as a regulator of axon branching in the growth cone of grasshopper embryos . To date, more than 20 semaphorin members have been discovered in viruses, invertebrates, and vertebrates . In addition to acting as guidance cues for axon growth in the nervous system, semaphorins have been implicated in many other systems, such as immune responses, tumor angiogenesis, bone development and homeostasis, and cardiovascular development …”

“…S emaphorins are a family of secreted and membranebound molecules that play critical functions in diverse biological processes. [1][2][3][4][5][6][7][8][9] SEMA1A/Fasciclin IV is the founding member of the semaphorin family and was first reported in 1992 as a regulator of axon branching in the growth cone of grasshopper embryos. 10 To date, more than 20 semaphorin members have been discovered in viruses, invertebrates, and vertebrates.…”

“…10 To date, more than 20 semaphorin members have been discovered in viruses, invertebrates, and vertebrates. 3,5,11 In addition to acting as guidance cues for axon growth in the nervous system, semaphorins have been implicated in many other systems, such as immune responses, tumor angiogenesis, bone development and homeostasis, and cardiovascular development. [1][2][3][4][5][6][7][8][9] Semaphorins are categorized into 8 classes.…”

Plexin-B2 is a key regulator of cell mechanics during multicellular organization

“…Plexin-B2 also regulates cerebellar granule cell migration, corticogenesis, as well as proliferation and migration of neuroblasts in postnatal rostral migratory stream 9,10,12,13 . Besides neurodevelopment, plexins critically regulate cellular interactions in a wide range of contexts, including vascular development, immune system activation, bone homeostasis, as well as renal epithelial morphogenesis and repair [14][15][16][17][18][19][20][21][22][23] .…”