Immune plexins and semaphorins: old proteins, new immune functions

Abstract

Plexins and semaphorins are a large family of proteins that are involved in cell movement and response. The importance of plexins and semaphorins has been emphasized by their discovery in many organ systems including the nervous (Nkyimbeng-Takwi and Chapoval, 2011; McCormick and Leipzig, 2012; Yaron and Sprinzak, 2012), epithelial (Miao et al., 1999; Fujii et al., 2002), and immune systems (Takamatsu and Kumanogoh, 2012) as well as diverse cell processes including angiogenesis (Serini et al., 2009; Sakurai et al., 2012), embryogenesis (Perala et al., 2012), and cancer (Potiron et al., 2009; Micucci et al., 2010). Plexins and semaphorins are transmembrane proteins that share a conserved extracellular semaphorin domain (Hota and Buck, 2012). The plexins and semaphorins are divided into four and eight subfamilies respectively based on their structural homology. Semaphorins are relatively small proteins containing the extracellular semaphorin domain and short intra-cellular tails. Plexins contain the semaphorin domain and long intracellular tails (Hota and Buck, 2012). The majority of plexin and semaphorin research has focused on the nervous system, particularly the developing nervous system, where these proteins are found to mediate many common neuronal cell processes including cell movement, cytoskeletal rearrangement, and signal transduction (Choi et al., 2008; Takamatsu et al., 2010). Their roles in the immune system are the focus of this review.

Semaphorins and their Signaling Mechanisms

“…Perturbations of Sema signaling lead to abnormal immune cell migration in vitro and Sema knockout mice exhibit defective immune cell migration and function (reviewed in (13,174,175)). Recent studies have begun to uncover how immune cell migration events are mediated by Semas.…”

Knockdown Therapy for Treatment of Neoplasia in Draught Animals

“…Semaphorins have been found to function outside the nervous system serving as regulators of cell proliferation and migration and activators of lymphocytes (Kolodkin et al, 1993;Roney et al, 2013). Semaphorins and plexins are expressed in a variety of tissues besides the nervous system.…”

“…Finally, in vivo tumorangiogenic assays demonstrated that Sema4D alone can elicit a significant angiogenic response to promote tumor growth independently of VEGF. Semaphorin-plexin interactions have already been implicated in a variety of responses, including epithelial cell contact modification and branching morphogenesis, regulation of pathological angiogenesis, tissue organization during development, and immune responses (Kolodkin et al, 1993;Roney et al, 2013). Over expression of Sema4D may provide tumors with the potential to support much denser cell populations, thus limiting the space for large fluid-filled cysts, and favoring the formation of much smaller fluid-filled cysts.…”

Bidirectional Interactions of NK Cells and Dendritic Cells in Immunotherapy: Current and Future Perspective

“…New factor revealed will allow one to examine specifically its role in the NK-DC crosstalk in tumor environment. Semaphorins, a large family of secreted and membrane-bound proteins, have emerged to be an important regulator of several biological processes (such as vascular, cancer and neurodevelopment), cell morphology and leukocyte trafficking [56,57]. Of interest to us, Semaphorin 3E (its cognate receptor, plexin D1) has been reported to regulate negatively the secretion of IL-12 in DC, a primary cytokine to regulate NK cell activation [58].…”