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The Emerging Role of Class-3 Semaphorins and Their Neuropilin Receptors in Oncology

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The Emerging Role of Class-3 Semaphorins and Their Neuropilin Receptors in Oncology OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW The emerging role of class-3 semaphorins and their neuropilin receptors in oncology Patrick Nasarre Abstract: The semaphorins, discovered over 20 years ago, are a large family of secreted or Robert M Gemmill transmembrane and glycophosphatidylinositol -anchored proteins initially identified as axon Harry A Drabkin guidance molecules crucial for the development of the nervous system. It has now been estab- lished that they also play important roles in organ development and function, especially involving Division of Hematology-Oncology, The Hollings Cancer Center and the immune, respiratory, and cardiovascular systems, and in pathological disorders, including Medical University of South Carolina, cancer. During tumor progression, semaphorins can have both pro- and anti-tumor functions, Charleston, SC, USA and this has created complexities in our understanding of these systems. Semaphorins may affect tumor growth and metastases by directly targeting tumor cells, as well as indirectly by interacting with and influencing cells from the micro-environment and vasculature. Mechanisti- For personal use only. cally, semaphorins, through binding to their receptors, neuropilins and plexins, affect pathways involved in cell adhesion, migration, invasion, proliferation, and survival. Importantly, neuro- pilins also act as co-receptors for several growth factors and enhance their signaling activities, while class 3 semaphorins may interfere with this. In this review, we focus on the secreted class 3 semaphorins and their neuropilin co-receptors in cancer, including aspects of their signaling that may be clinically relevant. Keywords: semaphorin, neuropilin, plexin Introduction Cancers arise from normal cells through a series of genetic and epigenetic changes affecting the expression and function of driver oncogenes and tumor-suppressor genes. OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 137.108.70.13 on 15-Jan-2020 The pathways commonly altered in various neoplasms have proven to be crucial for regulation of cell-autonomous functions such as growth and cell cycle, cell survival and senescence, energy production, and immortality, as well as non-autonomous functions such as neo-angiogenesis and evasion of the immune response. Tumor progression is associated with invasive behavior and metastases as well as resistance to therapy. In addition, the recruitment of normal cells into the tumor microenvironment plays a major role by contributing to invasion and metastasis as well as to the proliferative potential of neoplastic cells. Semaphorins and their receptors impact many of these processes. Indeed, a recent review by Rehman and Tamagnone1 pointed out that the Correspondence: Harry A Drabkin semaphorin/plexin/neuropilin (NRP) signaling axis influences at least seven of ten Division of Hematology-Oncology, 2 173 Ashley Ave, Suite 102C BSB, ‘hallmarks’ of cancer proposed by Hanahan and Weinberg. Thus, the semaphorins, Charleston, SC 29425, USA plexins and NRPs constitute a regulatory system deeply intertwined with multiple func- Tel +1 843 792 4879 tions critical to the pathology of tumors and, as such, present significant opportunities Fax +1 843 792 0644 Email [email protected] for novel therapeutic interventions. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2014:7 1663–1687 1663 Dovepress © 2014 Nasarre et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/OTT.S37744 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Powered by TCPDF (www.tcpdf.org) 1 / 1 Nasarre et al Dovepress The semaphorin family contains ∼25 members Early studies revealed that dimerization is required for grouped into eight classes based on structural similarities. semaphorin function. The Sema domain, the Ig domain, Semaphorins are secreted or anchored to the plasma and disulfide bridges established between the C-terminal membrane by either a glycophosphatidylinositol (GPI) BDs are essential for dimerization.4,5 Proteolytic cleavage modification at the C-terminus or a transmembrane domain. of a C-terminal pro-peptide at RXXXR consensus sites by Initially described as collapsins, due to their influence on furin-like proteases is also necessary for class 3 semaphorin migrating neural growth cones, they all share a common function. This cleavage is believed to result in the stabiliza- and highly conserved 500 amino acid Sema domain. Aside tion of active semaphorin dimers, as well as the formation of from their function as guidance molecules in the central a C-terminal basic motif that has high affinity for an acidic nervous system (CNS), semaphorins, NRPs, and plexins groove in the extracellular domains of NRP1 and NRP2.6 The have been increasingly associated with both normal and resulting processed end sequence resembles the C-terminus pathological processes. Normal functions include organ of vascular endothelial growth factor (VEGF), as well as development, tissue repair, immune responses, angiogen- tuftsin, an NRP-binding peptide. The crystal structure of the esis, and bone metabolism. The class 3 semaphorins are the PSI and Ig-like domains has recently been described, giving only group of secreted soluble proteins in the semaphorin new insights into the mode of interaction between class 3 family, which, as described later, present many advantages semaphorins, NRPs, and plexins.7 Unlike other semaphorins, from a therapeutic standpoint. In addition, they uniquely SEMA3s usually cannot directly bind to plexins, rather and specifically interact with NRPs. Consequently, requiring NRPs to stabilize a heterotrimeric complex. Low- semaphorin–NRP interaction prevents the binding of mul- resolution crystal structure of a semaphorin–NRP–plexin tiple growth factors to NRPs and blocks the activation of complex revealed that SEMA3 dimers bind to NRP dimers downstream signaling pathways, affecting, among other with plexins positioned on each side.7 Higher-order struc- aspects, tumor growth, tumor-associated angiogenesis, and tures can also be formed through interactions involving the metastatic spread. This review specifically focuses on the NRP C (MAM)-domains or transmembrane segments (see For personal use only. role of class 3 semaphorins and NRPs in cancer as a major below for NRP structure). As a consequence, higher-order pathology associated with dysfunction of these pathways. multimers and plexin clustering could form, possibly result- In particular, we review the current knowledge about these ing in enhanced semaphorin signaling. two groups of molecules, along with potential therapeutic strategies to target them. Neuropilins NRP1 and 2 are 130 kDa type-1 transmembrane glyco- Structure, signaling, and function proteins that share 44% sequence identity at the amino of class 3 semaphorins and their acid level (Figure 1B). Their extracellular domain contains receptors an N-terminal signal peptide, two calcium-binding C1r/ C1s/Uegf/Bmp1 (CUB) domains (designated a1 and a2), OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 137.108.70.13 on 15-Jan-2020 Structure Class 3 semaphorins two coagulation factor V/VIII-like discoidin domains (b1 The seven members of the class 3 semaphorins, SEMA3A and b2), and a juxta-membrane meprin/A5-antigen/ptp-Mu through SEMA3G, are secreted, in contrast to all other classes (MAM or c) domain.8–10 The ‘a1a2’ region interacts with that are either transmembranous or anchored to the membrane the Sema domain of SEMA3s,11 while the ‘b1’ domain via GPI modification. Consequently, SEMA3s can have both interacts with the semaphorin PSI and Ig-like domains.12 autocrine and paracrine functions. They are defined by a 500 Of note, the affinity for NRP1 and 2 varies specifically amino acid Sema domain, which is common to semaphorins, from one SEMA3 to another; NRP1 preferentially interacts plexins, and the oncogenic receptor tyrosine kinases, MET with SEMA3A, SEMA3B, and SEMA3E; NRP2 has higher and RON (Figure 1A). The Sema domain, with its 7-bladed affinity for SEMA3F and SEMA3G, while SEMA3C binds beta-propeller structure, is crucial for protein–protein interac- both NRPs with similar affinity.12–16 NRP ‘b1b2’ domains tions and is conserved across species.3 Class 3 semaphorins also interact with several growth factors containing hepa- are characterized by several additional conserved domains rin-binding domains,17 including VEGFA-D,18–20 placenta including the plexin, semaphorins, and integrin (PSI) domain, growth factor (PlGF)-2,21 fibroblast growth factor (FGF),22 an immunoglobulin (Ig)-like and a C-terminal basic domain galectin,23 hepatocyte growth factor (HGF),22,24–26 platelet- (BD). derived growth factor (PDGF),27–32 and transforming growth 1664 submit your manuscript | www.dovepress.com OncoTargets and Therapy 2014:7 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Potential of semaphorin signaling in oncology EXT INT A Class 3 semaphorin B Neuropilin SEA
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