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Gera Neufeld, Yelena Mumblat, Tanya Smolkin, Shira Toledano, Inbal Nir-Zvi, Keren Ziv, Ofra Kessler
The semaphorins were initially characterized as repulsive axon guidance factors. However, they are currently also recognized as important regulators of diverse biological processes which include regulation of immune responses, angiogenesis, organogenesis, and a variety of additional physiological and developmental functions. The semaphorin family consists of more than 20 genes divided into seven subfamilies, all of which contain the sema domain signature. They usually transduce signals by activation of receptors belonging to the plexin family, either directly, or indirectly following the binding of some semaphorins to receptors of the neuropilin family which subsequently associate with plexins...
November 2016: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
Lionel A T Meyer, Justine Fritz, Marie Pierdant-Mancera, Dominique Bagnard
The Semaphorin/Neuropilin/Plexin (SNP) complexes control a wide range of biological processes. Consistently, activity deregulation of these complexes is associated with many diseases. The increasing knowledge on SNP had in turn validated these molecular complexes as novel therapeutic targets. Targeting SNP activities by small molecules, antibodies and peptides or by soluble Semaphorins have been proposed as new therapeutic approach. This review is focusing on the latest demonstration of this potential and discusses some of the key questions that need to be addressed before translating SNP targeting into clinically relevant approaches...
December 1, 2016: Cell Adhesion & Migration
Yanjie Lu, Qian Xu, Lei Chen, Yanzhen Zuo, Shaochen Liu, Yatao Hu, Xiaoru Li, Yuhong Li, Xiangyang Zhao
The semaphorin and plexin family of ligands and receptor proteins provides important axon growth and guidance cues required for development. In recent years, studies have expanded their role in the regulation of cardiac morphogenesis and tumorigenesis. However, the mechanism responsible for their role in regulating cancer development and progression has not been clarified. In the present study, semaphorin 6D (Sema6D) and its receptor plexin-A1 were identified to be expressed at high levels in vascular epithelial cells within gastric cancer, and were positively correlated with vascular endothelial growth factor receptor 2 (VEGFR2)...
November 2016: Oncology Letters
Z Shi, H Liang, Y Hou
Although some novel antimicrobial peptides (AMP) have been successfully isolated from Bactrocera dorsalis Hendel, the mechanisms underlying the induction of these peptides are still elusive. The homolog of NF-κB transcription factor Relish, designated as BdRelish, was cloned from B. dorsalis. The full length cDNA of BdRelish is 3954 bp with an open reading frame that encodes 1013 amino acids. Similar to Drosophila Relish and the mammalian p100, it is a compound protein containing a conserved Rel homology domain, an IPT (Ig-like, plexins, transcription factors) domain and an IκB-like domain (four ankyrin repeats), the nuclear localization signal RKRRR is also detected at the residues 449-453, suggesting that it has homology to Relish and it is a member of the Rel family of transcription activator proteins...
November 22, 2016: Bulletin of Entomological Research
Julia Kunath, Nicolas Delaroque, Michael Szardenings, Ines Neundorf, Rainer H Straub
AIMS: In rheumatoid arthritis and collagen type II arthritis (CIA), sympathetic nerve fibers get lost in inflamed tissue. The process is probably induced by nerve repellent factors like semaphorin 3F (SEMA3F). Repulsion of sympathetic nerve fibers in inflamed tissue has proinflammatory effects due to the loss of anti-inflammatory neurotransmitters. We hypothesized that design molecules like antibodies and specific peptides that inhibit nerve fiber repulsion can ameliorate CIA. MATERIALS AND METHODS: Two blocking antibodies were used and four blocking peptides were generated using the phage display technique with the targets of SEMA3F and plexin-A2...
November 14, 2016: Life Sciences
Markus F Bartels, Patrick R Winterhalter, Jin Yu, Yan Liu, Mark Lommel, Frank Möhrlen, Huaiyu Hu, Ten Feizi, Ulrika Westerlind, Thomas Ruppert, Sabine Strahl
Protein O-mannosylation is a post-translational modification essential for correct development of mammals. In humans, deficient O-mannosylation results in severe congenital muscular dystrophies often associated with impaired brain and eye development. Although various O-mannosylated proteins have been identified in the recent years, the distribution of O-mannosyl glycans in the mammalian brain and target proteins are still not well defined. In the present study, rabbit monoclonal antibodies directed against the O-mannosylated peptide YAT(α1-Man)AV were generated...
2016: PloS One
Yan-Qiu Liu, Xiao-Fei Han, Jun-Xia Bo, Hui-Peng Ma
Bone remodeling balance is maintained by tight coupling of osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Thus, agents with the capacity to regulate osteoblastogenesis and osteoclastogenesis have been investigated for therapy of bone-related diseases such as osteoporosis. In this study, we found that wedelolactone, a compound isolated from Ecliptae herba, and a 9-day incubation fraction of conditioned media obtained from wedelolactone-treated bone marrow mesenchymal stem cell (BMSC) significantly inhibited tartrate-resistant acid phosphatase (TRAP) activity in RANKL-stimulated osteoclastic RAW264...
2016: Frontiers in Pharmacology
Céline Hendricks, Johanne Dubail, Laura Brohée, Yves Delforge, Alain Colige, Christophe Deroanne
Neuropilin-1 (NRP1) is a transmembrane protein acting as a co-receptor for several growth factors and interacting with other proteins such as integrins and plexins/semaphorins. It is involved in axonal development, angiogenesis and cancer progression. Its primary mRNA is subjected to alternative splicing mechanisms generating different isoforms, some of which lack the transmembrane domain and display antagonist properties to NRP1 full size (FS). NRP1 is further post-translationally modified by the addition of glycosaminoglycans (GAG) side chains through an O-glycosylation site at serine612...
2016: PloS One
Ricardo H Paap, Saskia Oosterbroek, Cindy M R J Wagemans, Lars von Oerthel, Raymond D Schellevis, Annemarie J A Vastenhouw-van der Linden, Marian J A Groot Koerkamp, Marco F M Hoekman, Marten P Smidt
The forkhead transcription factor FoxO6 is prominently expressed during development of the murine neocortex. However, its function in cortical development is as yet unknown. We now demonstrate that cortical development is altered in FoxO6(+/-) and FoxO6(-/-) mice, showing migrating neurons halted in the intermediate zone. Using a FoxO6-directed siRNA approach, we substantiate the requirement of FoxO6 for a correct radial migration in the developing neocortex. Subsequent genome-wide transcriptome analysis reveals altered expression of genes involved in cell adhesion, axon guidance, and gliogenesis upon silencing of FoxO6 We then show that FoxO6 binds to DAF-16-binding elements in the Plexin A4 (Plxna4) promoter region and affects Plxna4 expression...
October 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
Akira Nukazuka, Shin Takagi
A small model animal Caenorhabditis elegans is particularly suitable for genetic analysis, but cell-type-specific biochemistry is a formidable task in this organism. Here we describe techniques utilizing transgenic C. elegans strains expressing epitope-tagged proteins for analyzing biochemical events, such as protein phosphorylation and formation of protein complex, in a small number of a specific group of cells at a defined stage of development. The techniques are useful for elucidating that C. elegans semaphorin-plexin signaling systems regulate epidermal morphogenesis through modulating TOR signaling and its downstream targets...
2017: Methods in Molecular Biology
Hua Zhou, Ying-Hua Yang, John R Basile
The semaphorins and plexins comprise a family of cysteine-rich cell surface and secreted proteins originally shown to control nerve growth and the immune response, but that have recently been implicated in a wide variety of developmental and pathological processes that are influenced by cell adhesion and migration. Along those lines, our group and others have found that Semaphorin 4D (SEMA4D) plays an important role in angiogenesis by promoting chemotaxis of endothelial cells, which express its receptor, Plexin-B1...
2017: Methods in Molecular Biology
Chiara Camillo, Noemi Gioelli, Federico Bussolino, Guido Serini
Semaphorins (SEMA) are chemorepulsive guidance cues that, acting through plexin receptors, inhibit integrin-mediated cell adhesion to the extracellular matrix. The ensuing cell retraction and collapse is a key biological event downstream of SEMA/plexin signaling that is however hard to precisely quantify. Here, we describe a quantitative approach that allows monitoring over time the evolution of SEMA3E/plexin D1-elicited endothelial cell collapse. This method exploits the xCELLigence platform, an electrical impedance-based system in which microelectronic sensor arrays are integrated into the bottom of microplate wells...
2017: Methods in Molecular Biology
Atsuko Sakurai, Colleen L Doçi, J Silvio Gutkind
Semaphorins are a family of membrane-bound and secreted type of proteins which were initially identified as chemorepulsive axon guidance molecules. Plexins and neuropilins are two major receptor families of semaphorins, and their common downstream targets are the actin cytoskeleton and cell-to-extracellular matrix adhesions. Semaphorins promote the collapse of growth cones by inducing rapid changes in the cytoskeleton and disassembly of focal adhesion structures. When transfected with appropriate receptors, non-neuronal COS-7 cells exhibit a similar cell collapse phenotype upon semaphorin stimulation...
2017: Methods in Molecular Biology
Taehong Yang, Jonathan R Terman
Protein phosphorylation is one of the widely used posttranslational modifications that alter protein function in vivo. We recently showed phosphorylation of Drosophila Plexin A by cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) and subsequent inhibition of plexin-mediated repulsive guidance. This phosphorylation occurs in the active site of the plexin GTPase-activating protein (GAP) domain, which in turn inhibits endogenous GAP activity toward Ras/Rap family small GTP-binding proteins by recruiting the phospho-serine/threonine-binding protein 14-3-3ε...
2017: Methods in Molecular Biology
Thomas Worzfeld, Jakub M Swiercz
Plexins comprise a family of transmembrane receptors for semaphorins. Plexins of the B- and D-subfamily interact with the receptor tyrosine kinase ErbB-2, and this interaction has been shown to be functionally relevant for various biological processes including tumor metastasis and bone formation. Binding of semaphorins to B- and D-subfamily plexins results in the activation of ErbB-2, which in turn phosphorylates these plexins. This phosphorylation triggers the activation of the small GTPases RhoA and RhoC downstream of B-subfamily plexins...
2017: Methods in Molecular Biology
Jimok Yoon, Ruei-Jiun Hung, Jonathan R Terman
The MICALs are a family of phylogenetically conserved cytoplasmic proteins that modulate numerous cellular behaviors and play critical roles in semaphorin-plexin signaling. Our recent results have revealed that the MICALs are an unusual family of actin regulatory proteins that use actin filaments (F-actin) as a direct substrate-controlling F-actin dynamics via stereospecific oxidation of conserved methionine (Met44 and Met47) residues within actin. In particular, the MICALs have a highly conserved flavoprotein monooxygenase (redox) enzymatic domain in their N-terminus that directly oxidizes and destabilizes F-actin...
2017: Methods in Molecular Biology
Heath G Pascoe, Yuxiao Wang, Xuewu Zhang
Plexins are cell surface receptors that bind semaphorins and regulate essential processes such as axon guidance and angiogenesis. The cytoplasmic regions of plexins contain a functionally essential GTPase-activating protein (GAP) domain, which initiates downstream signaling by specifically inactivating the Rap GTPase. Here we describe the methods for expression and purification of the plexin cytoplasmic region in E. coli, and characterization of its GAP activity using a photometric assay. We also provide a protocol for measuring GAP activity of single-chain constructs with Rap covalently linked to the plexin cytoplasmic region...
2017: Methods in Molecular Biology
Jeannine Muller-Greven, SoonJeung Kim, Prasanta K Hota, Yufeng Tong, Susmita Borthakur, Matthias Buck
Plexins are unique, as they are the first example of a transmembrane receptor that interacts directly with small GTPases, a family of proteins that are essential for cell motility and proliferation/survival. We and other laboratories have determined the structure of the Rho GTPase-binding domain (RBD) of several plexins and also of the entire intracellular region of plexin-B1. Structures of plexin complexes with Rho GTPases, Rac1 and Rnd1, and a structure with a Ras GTPase, Rap1b, have also been solved. The relationship between plexin-Rho and plexin-Ras interactions is still unclear and in vitro biophysical experiments that characterize the protein interactions of purified components play an important role in advancing our understanding of the molecular mechanisms that underlie the function of plexin...
2017: Methods in Molecular Biology
Matthew W Parker, Craig W Vander Kooi
The semaphorins are an essential family of axon guidance molecules that can be either secreted or are transmembrane proteins. Class 3 semaphorin (Sema3) family members are secreted and provide long-range guidance cues through two receptor families: neuropilins (Nrp) and plexins. Nrp is uniquely required for high-affinity Sema3 binding and signaling. Therefore, characterizing the molecular details of the Sema3/Nrp interaction is important for understanding the broader physiological and pathological role of the Sema3 family of proteins...
2017: Methods in Molecular Biology
Terukazu Nogi, Emiko Mihara, Norihisa Yasui, Junichi Takagi
Plexins are type I membrane proteins that function as receptors for semaphorins. All of the known plexins contain a large globular domain, termed the sema domain, in the N-terminal extracellular region, which interacts with semaphorins during signal transduction. Here, we describe procedures for protein production and purification that we utilized in the crystallographic study of the mouse Plexin A2 (mPlxnA2) extracellular fragment, including the sema domain. A mutant mammalian cell line, HEK293S GnTI(-), was used as an expression host for the production of a crystallizable-quality mPlxnA2 fragment, which contains several N-glycosylation sites and disulfide bonds...
2017: Methods in Molecular Biology
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