Semaphorins and their Signaling Mechanisms

Abstract

Semaphorins are extracellular signaling proteins that are essential for the development and maintenance of many organs and tissues. The more than 20-member semaphorin protein family includes secreted, transmembrane and cell surface-attached proteins with diverse structures, each characterized by a single cysteine-rich extracellular sema domain, the defining feature of the family. Early studies revealed that semaphorins function as axon guidance molecules, but it is now understood that semaphorins are key regulators of morphology and motility in many different cell types including those that make up the nervous, cardiovascular, immune, endocrine, hepatic, renal, reproductive, respiratory and musculoskeletal systems, as well as in cancer cells. Semaphorin signaling occurs predominantly through Plexin receptors and results in changes to the cytoskeletal and adhesive machinery that regulate cellular morphology. While much remains to be learned about the mechanisms underlying the effects of semaphorins, exciting work has begun to reveal how semaphorin signaling is fine-tuned through different receptor complexes and other mechanisms to achieve specific outcomes in various cellular contexts and physiological systems. These and future studies will lead to a more complete understanding of semaphorin-mediated development and to a greater understanding of how these proteins function in human disease.

Keywords: Axon guidance; Cell morphology; Cellular guidance; Inhibition; Motility; Navigation; Neuropilin; Plexin; Repulsive signaling; Semaphorin; Signaling to the cytoskeleton.

Figure 1. The Semaphorin Protein Family

Semaphorin protein family members are grouped into 8 classes based on their domain structure. Class 1 and 2 Semas and Sema5c are found in invertebrates, Class 3–7 Semas are found in vertebrates and Class V Semas are found in viruses. Plexin receptors, the predominant receptors for Semas, are grouped into 4 classes (A–D) and each plexin receptor class interacts with a particular Sema class or classes to mediate signaling. A number of other membrane-associated receptors and co-receptors are also important for Sema signal transduction. These proteins directly bind Semas and initiate signaling (e.g., integrins), act as ligand binding co-receptors (e.g., Npn1,2), and/or work as part of multimeric receptor complexes (e.g., RTKs). Proteins functioning downstream of receptor complexes to mediate Sema signaling are not shown (see text). At least some transmembrane Semas also function as receptors in reverse signaling (e.g., leftward arrows) and participate in cis (within the same cell) interactions with plexin receptors (e.g., asterisk). Semi-transparency of Class V semaphorin Ig and PSI domains indicates that these domains are present in some, but not all, viral semaphorins. Sema (semaphorin domain), PSI (plexin-semaphorin-integrin domain), Ig (immunoglobulin domain), Basic (basic domain), PDZ (PDZ domain), TSP (Thrombospondin domain), GPI (glycosylphosphatidylinositol linkage), RTK (receptor tyrosine kinase), Npn1 (Neuropilin 1), Npn2 (Neuropilin 2), CAM (cell adhesion molecule) Tim-2 (T-cell Ig and mucin domain containing protein 2), CD72 (B cell differentiation antigen CD72), CLCP1 (CUB, LCCL-homology, Coagulation factor V/VIII homology domains protein 1), TREM2 (Triggering Receptor Expressed on Myeloid Cells 2), DAP12 (DNAX activating protein of 12 kDa)((1,12,23,46,232,233) and references therein.