The Experts below are selected from a list of 7068 Experts worldwide ranked by ideXlab platform
Luca Tamagnone - One of the best experts on this subject based on the ideXlab platform.
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Semaphorin Signaling in Cancer-Associated Inflammation
'MDPI AG', 2019Co-Authors: Giulia Franzolin, Luca TamagnoneAbstract:The inflammatory and immune response elicited by the growth of cancer cells is a major element conditioning the tumor microenvironment, impinging on disease progression and patients’ prognosis. Semaphorin receptors are widely expressed in inflammatory cells, and their ligands are provided by tumor cells, featuring an intense signaling cross-talk at local and systemic levels. Moreover, diverse Semaphorins control both cells of the innate and the antigen-specific immunity. Notably, Semaphorin signals acting as inhibitors of anti-cancer immune response are often dysregulated in human tumors, and may represent potential therapeutic targets. In this mini-review, we provide a survey of the best known Semaphorin regulators of inflammatory and immune cells, and discuss their functional impact in the tumor microenvironment
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Transmembrane Semaphorins, forward and reverse signaling: have a look both ways
Cellular and Molecular Life Sciences, 2016Co-Authors: Chiara Battistini, Luca TamagnoneAbstract:Semaphorins are signaling molecules playing pivotal roles not only as axon guidance cues, but are also involved in the regulation of a range of biological processes, such as immune response, angiogenesis and invasive tumor growth. The main functional receptors for Semaphorins are plexins, which are large single-pass transmembrane molecules. Semaphorin signaling through plexins—the “classical” forward signaling—affects cytoskeletal remodeling and integrin-dependent adhesion, consequently influencing cell migration. Intriguingly, Semaphorins and plexins can interact not only in trans , but also in cis , leading to differentiated and highly regulated signaling outputs. Moreover, transmembrane Semaphorins can also mediate a so-called “reverse” signaling, by acting not as ligands but rather as receptors, and initiate a signaling cascade through their own cytoplasmic domains. Semaphorin reverse signaling has been clearly demonstrated in fruit fly Sema1a, which is required to control motor axon defasciculation and target recognition during neuromuscular development. Sema1a invertebrate Semaphorin is most similar to vertebrate class-6 Semaphorins, and examples of Semaphorin reverse signaling in mammalians have been described for these family members. Reverse signaling is also reported for other vertebrate Semaphorin subsets, e.g. class-4 Semaphorins, which bear potential PDZ-domain interaction motifs in their cytoplasmic regions. Therefore, thanks to their various signaling abilities, transmembrane Semaphorins can play multifaceted roles both in developmental processes and in physiological as well as pathological conditions in the adult.
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p190 rho gtpase activating protein associates with plexins and it is required for Semaphorin signalling
Journal of Cell Science, 2005Co-Authors: Davide Barberis, Simona Corso, Paolo M. Comoglio, Stefania Artigiani, Andrea Casazza, Raffaella Sordella, Jeff Settleman, Luca TamagnoneAbstract:Plexins are transmembrane receptors for Semaphorins, guiding cell migration and axon extension. Plexin activation leads to the disassembly of integrin-based focal adhesive structures and to actin cytoskeleton remodelling and inhibition of cell migration; however, the underlying molecular mechanisms are unclear. We consistently observe a transient decrease of cellular RhoA-GTP levels upon plexin activation in adherent cells. One of the main effectors of RhoA downregulation is p190, a ubiquitously expressed GTPase activating protein (GAP). We show that, in p190-deficient fibroblasts, the typical functional activities mediated by plexins (such as cell collapse and inhibition of integrin-based adhesion) are blocked or greatly impaired. Notably, the functional response can be rescued in these cells by re-expressing exogenous p190, but not a mutant form specifically lacking RhoGAP activity. We furthermore demonstrate that Semaphorin function is blocked in epithelial cells, primary endothelial cells and neuroblasts upon treatment with small interfering RNAs that knockdown p190 expression. Finally, we show that p190 transiently associates with plexins, and its RhoGAP activity is increased in response to Semaphorin stimulation. We conclude that p190-RhoGAP is crucially involved in Semaphorin signalling to the actin cytoskeleton, via interaction with plexins.
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sema4d induces angiogenesis through met recruitment by plexin b1
Blood, 2005Co-Authors: Paolo Conrotto, Simona Corso, Paolo M. Comoglio, Luca Tamagnone, Donatella Valdembri, Guido Serini, Federico Bussolino, Silvia GiordanoAbstract:Semaphorins, a large family of membrane-bound and secreted proteins, signal through their transmembrane receptors, the plexins. Semaphorins and plexins share structural homologies with scatter factor receptors, a family of tyrosine kinase receptors for which Met is the prototype. Semaphorins have been studied primarily in the developing nervous system, where they act as repelling cues in axon guidance. However, they are widely expressed in several tissues, and their role in epithelial morphogenesis has been recently established. Not much is known about their role in angiogenesis, a key step during embryonic development and adulthood. Here we demonstrate that a Semaphorin, Sema4D, is angiogenic in vitro and in vivo and that this effect is mediated by its high-affinity receptor, Plexin B1. Moreover, we prove that biologic effects elicited by Plexin B1 require coupling and activation of the Met tyrosine kinase. In sum, we identify a proangiogenic Semaphorin and provide insight about the signaling machinery exploited by Plexin B1 to control angiogenesis.
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plexin b3 is a functional receptor for Semaphorin 5a
EMBO Reports, 2004Co-Authors: Stefania Artigiani, Paolo Conrotto, Silvia Giordano, Paolo M. Comoglio, Davide Barberis, Pietro Fazzari, Giorgio F Gilestro, Luca TamagnoneAbstract:Semaphorins are a large family of molecular cues implicated in neural development and in a variety of functions outside the nervous system. Semaphorin 5A (Sema5A) is a transmembrane Semaphorin, containing seven thrombospondin type-1 repeats, which was recently found to control axon guidance. Here we show that plexin-B3 is a high-affinity receptor specific for Sema5A. We further demonstrate that plexin-B3 activation by Sema5A mediates functional responses in plexin-B3-expressing cells (either fibroblasts, epithelial and primary endothelial cells). In addition, Sema5A can trigger the intracellular signalling of the hepatocyte growth factor/scatter factor receptor, Met, associated in a complex with plexin-B3. We thus conclude that Sema5A is able to elicit multiple functional responses through its receptor plexin-B3.
Hwaijong Cheng - One of the best experts on this subject based on the ideXlab platform.
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axon pruning and synaptic development how are they per plexin
The Neuroscientist, 2006Co-Authors: Kathryn E Waimey, Hwaijong ChengAbstract:During the development of the nervous system, neurons must first migrate to their appropriate locations and then send out axons to make connections. Various environmental cues guide these migrating neurons and growing axons. After axons reach their target regions, neuronal contacts are created through the formation of synapses. Because excess axonal branches and synaptic contacts are often formed during early development, they are pruned or eliminated at later stages to create specific neuronal connections. Several groups of ligand-receptor pairs have been identified to regulate each of these cellular events. Evidence also indicates that these same molecules may be used in multiple developmental processes. Here, we discuss Semaphorins and plexins, the largest family of axon guidance ligand-receptor pairs. Because the roles of Semaphorins in neuronal migration and axonal repulsion have been extensively reviewed, we will focus on plexin receptors. We will discuss how Semaphorin signals are specifically pass...
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axon pruning and synaptic development how are they per plexin
The Neuroscientist, 2006Co-Authors: Kathryn E Waimey, Hwaijong ChengAbstract:During the development of the nervous system, neurons must first migrate to their appropriate locations and then send out axons to make connections. Various environmental cues guide these migrating neurons and growing axons. After axons reach their target regions, neuronal contacts are created through the formation of synapses. Because excess axonal branches and synaptic contacts are often formed during early development, they are pruned or eliminated at later stages to create specific neuronal connections. Several groups of ligand-receptor pairs have been identified to regulate each of these cellular events. Evidence also indicates that these same molecules may be used in multiple developmental processes. Here, we discuss Semaphorins and plexins, the largest family of axon guidance ligand-receptor pairs. Because the roles of Semaphorins in neuronal migration and axonal repulsion have been extensively reviewed, we will focus on plexin receptors. We will discuss how Semaphorin signals are specifically passed through these receptors into cells and how plexins mediate their newly identified roles in axon pruning and synaptic development.
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plexin a3 mediates Semaphorin signaling and regulates the development of hippocampal axonal projections
Neuron, 2001Co-Authors: Hwaijong Cheng, Anil Bagri, Elke Stein, Samuel J PleasureAbstract:Plexins are receptors implicated in mediating signaling by Semaphorins, a family of axonal chemorepellents. The role of specific plexins in mediating Semaphorin function in vivo has not, however, yet been examined in vertebrates. Here, we show that plexin-A3 is the most ubiquitously expressed plexin family member within regions of the developing mammalian nervous system known to contain Semaphorin-responsive neurons. Using a chimeric receptor construct, we provide evidence that plexin-A3 can transduce a repulsive signal in growth cones in vitro. Analysis of plexin-A3 knockout mice shows that plexin-A3 contributes to Sema3F and Sema3A signaling and that plexin-A3 regulates the development of hippocampal axonal projections in vivo.
Corey S Goodman - One of the best experts on this subject based on the ideXlab platform.
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the transmembrane protein off track associates with plexins and functions downstream of Semaphorin signaling during axon guidance
Neuron, 2001Co-Authors: Margaret L Winberg, Paolo M. Comoglio, Luca Tamagnone, Jianwu Bai, Denise J Montell, Corey S GoodmanAbstract:The Plexin family of transmembrane proteins appears to function as repulsive receptors for most if not all Semaphorins. Here, we use genetic and biochemical analysis in Drosophila to show that the transmembrane protein Off-track (OTK) associates with Plexin A, the receptor for Sema 1a, and that OTK is a component of the repulsive signaling response to Semaphorin ligands. In vitro, OTK associates with Plexins. In vivo, mutations in the otk gene lead to phenotypes resembling those of loss-of-function mutations of either Sema1a or PlexA. The otk gene displays strong genetic interactions with Sema1a and PlexA, suggesting that OTK and Plexin A function downstream of Sema 1a.
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plexins are a large family of receptors for transmembrane secreted and gpi anchored Semaphorins in vertebrates
Cell, 1999Co-Authors: Luca Tamagnone, Margaret L Winberg, Corey S Goodman, Hang Chen, Alain Chedotal, Stefania Artigiani, Guo Li Ming, Hongjun Song, Muming PooAbstract:In Drosophila, plexin A is a functional receptor for Semaphorin-1a. Here we show that the human plexin gene family comprises at least nine members in four subfamilies. Plexin-B1 is a receptor for the transmembrane Semaphorin Sema4D (CD100), and plexin-C1 is a receptor for the GPI-anchored Semaphorin Sema7A (Sema-K1). Secreted (class 3) Semaphorins do not bind directly to plexins, but rather plexins associate with neuropilins, coreceptors for these Semaphorins. Plexins are widely expressed: in neurons, the expression of a truncated plexin-A1 protein blocks axon repulsion by Sema3A. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro. We conclude that plexins are receptors for multiple (and perhaps all) classes of Semaphorins, either alone or in combination with neuropilins, and trigger a novel signal transduction pathway controlling cell repulsion.
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plexin a is a neuronal Semaphorin receptor that controls axon guidance
Cell, 1998Co-Authors: Margaret L Winberg, Paolo M. Comoglio, Jasprina N Noordermeer, Luca Tamagnone, Melanie K Spriggs, Corey S GoodmanAbstract:The Semaphorins comprise a large family of secreted and transmembrane proteins, some of which function as repellents during axon guidance. Semaphorins fall into seven subclasses. Neuropilins are neuronal receptors for class III Semaphorins. In the immune system, VESPR, a member of the Plexin family, is a receptor for a viral-encoded Semaphorin. Here, we identify two Drosophila Plexins, both of which are expressed in the developing nervous system. We present evidence that Plexin A is a neuronal receptor for class I Semaphorins (Sema 1a and Sema 1b) and show that Plexin A controls motor and CNS axon guidance. Plexins, which themselves contain complete Semaphorin domains, may be both the ancestors of classical Semaphorins and binding partners for Semaphorins.
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neuropilin 2 a novel member of the neuropilin family is a high affinity receptor for the Semaphorins sema e and sema iv but not sema iii
Neuron, 1997Co-Authors: Hang Chen, Alain Chedotal, Zhigang He, Corey S GoodmanAbstract:Abstract Semaphorins are a large family of secreted and transmembrane proteins, several of which are implicated in repulsive axon guidance. Neuropilin (neuropilin-1) was recently identified as a receptor for Collapsin-1/Semaphorin III/D (Sema III). We report the identification of a related protein, neuropilin-2, whose mRNA is expressed by developing neurons in a pattern largely, though not completely, nonoverlapping with that of neuropilin-1. Unlike neuropilin-1, which binds with high affinity to the three structurally related Semaphorins Sema III, Sema E, and Sema IV, neuropilin-2 shows high affinity binding only to Sema E and Sema IV, not Sema III. These results identify neuropilins as a family of receptors (or components of receptors) for at least one Semaphorin subfamily. They also suggest that the specificity of action of different members of this subfamily may be determined by the complement of neuropilins expressed by responsive cells.
Andreas W. Püschel - One of the best experts on this subject based on the ideXlab platform.
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Dual Functional Activity of Semaphorin 3B Is Required for Positioning the Anterior Commissure
Neuron, 2005Co-Authors: Falk Julien, Ahmad Bechara, Roberto Fiore, Homaira Nawabi, Heather Zhou, Carolina Hoyo-becerra, Muriel Bozon, Geneviève Rougon, Martin Grumet, Andreas W. PüschelAbstract:Chemorepulsion by Semaphorins plays a critical role during the development of neuronal projections. Although Semaphorin-induced chemoattraction has been reported in vitro, the contribution of this activity to axon pathfinding is still unclear. Using genetic and culture models, we provide evidence that both attraction and repulsion by Sema3B, a secreted Semaphorin, are critical for the positioning of a major brain commissural projection, the anterior commissure (AC). NrCAM, an immunoglobulin superfamily adhesion molecule of the L1 subfamily, associates with neuropilin-2 and is a component of a receptor complex for Sema3B and Sema3F. Finally, we show that activation of the FAK/Src signaling cascade distinguishes Sema3B-mediated attractive from repulsive axonal responses of neurons forming the AC, revealing a mechanism underlying the dual activity of this guidance cue.
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structure of the Semaphorin 3a receptor binding module
Neuron, 2003Co-Authors: Alexander Antipenko, Andreas W. Püschel, Juhapekka Himanen, Klaus Van Leyen, Vincenzo Nardidei, Jacob Lesniak, William A Barton, Kanagalaghatta R Rajashankar, Claudia Hoemme, Dimitar B NikolovAbstract:Abstract The Semaphorins are a large group of extracellular proteins involved in a variety of processes during development, including neuronal migration and axon guidance. Their distinctive feature is a conserved 500 amino acid Semaphorin domain, a ligand-receptor interaction module also present in plexins and scatter-factor receptors. We report the crystal structure of a secreted 65 kDa form of Semaphorin-3A (Sema3A), containing the full Semaphorin domain. Unexpectedly, the Semaphorin fold is a variation of the β propeller topology. Analysis of the Sema3A structure and structure-based mutagenesis data identify the neuropilin binding site and suggest a potential plexin interaction site. Based on the structure, we present a model for the initiation of Semaphorin signaling and discuss potential similarities with the signaling mechanisms of other β propeller cell surface receptors, such as integrins and the LDL receptor.
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plexin neuropilin complexes mediate repulsion by the axonal guidance signal Semaphorin 3a
Mechanisms of Development, 2000Co-Authors: Beate Rohm, Angelika Ottemeyer, Marion Lohrum, Andreas W. PüschelAbstract:In the developing nervous system axons navigate with great precision over large distances to reach their target areas. Chemorepulsive signals such as the Semaphorins play an essential role in this process. The effects of one of these repulsive cues, Semaphorin 3A (Sema3A), are mediated by the membrane protein neuropilin-1 (Npn-1). Recent work has shown that neuropilin-1 is essential but not sufficient to form functional Sema3A receptors and indicates that additional components are required to transduce signals from the cell surface to the cytoskeleton. Here we show that members of the plexin family interact with the neuropilins and act as co-receptors for Sema3A. Neuropilin/plexin interaction restricts the binding specificity of neuropilin-1 and allows the receptor complex to discriminate between two different Semaphorins. Deletion of the highly conserved cytoplasmic domain of Plexin-A1 or -A2 creates a dominant negative Sema3A receptor that renders sensory axons resistant to the repulsive effects of Sema3A when expressed in sensory ganglia. These data suggest that functional Semaphorin receptors contain plexins as signal-transducing and neuropilins as ligand-binding subunits.
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Molecular cloning and mapping of human Semaphorin F from the Cri-du-chat candidate interval.
Biochemical and Biophysical Research Communications, 1998Co-Authors: Andrew D. Simmons, Joan Overhauser, Andreas W. Püschel, John Douglas Mcpherson, Michael LovettAbstract:Abstract Cri-du-chat is a human contiguous gene deletion syndrome resulting from hemizygous deletions of chromosome 5p. Here we describe the isolation from within this interval of the human Semaphorin F (SEMAF) gene, a member of a family of proteins that has been implicated in axonal pathfinding. The humanSEMAFgene covers at least 10% of the deleted region and defines a new class within this large gene family characterized by the presence of seven type 1 thrombospondin repeats. Prominent expression of murine Semaphorin F (Semaf) was observed in the mouse brain, consistent with a role for Semaphorin F as a signaling molecule that guides axons or migrating neuronal precursors during development. The known functions of Semaphorins and the interesting pattern of expression forSemafsuggest that haploinsufficiency forSEMAFmay disrupt normal brain development and might lead to some of the features of Cri-du-chat.
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the chemorepulsive activity of secreted Semaphorins is regulated by furin dependent proteolytic processing
The EMBO Journal, 1997Co-Authors: Ralf H Adams, Marion Lohrum, Andreas Klostermann, Heinrich Betz, Andreas W. PüschelAbstract:The Semaphorins are a large group of cell surface and secreted proteins implicated in axonal pathfinding. Here we show that the secreted mouse Semaphorin D (SemD) is synthesized as an inactive precursor (proSemD) and becomes repulsive for sensory and sympathetic neurites upon proteolytic cleavage. ProSemD processing can be blocked completely by an inhibitor selective for furin-like endoproteases or mutagenesis of three conserved dibasic cleavage sites. Its C-terminal pro-peptide contains a processing signal that is essential for SemD to acquire its full repulsive activity. SemD processing is regulated during the embryonic development of the mouse and determines the magnitude of its repulsive activity. Similarly to SemD, the secreted Semaphorins SemA and SemE display repulsive properties that are regulated by processing. Our data suggest that differential proteolytic processing determines the repulsive potency of secreted Semaphorins and implicate proteolysis as an important regulatory mechanism in axonal pathfinding.
Alex L. Kolodkin - One of the best experts on this subject based on the ideXlab platform.
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a forward genetic screen in mice identifies sema3ak108n which binds to neuropilin 1 but cannot signal
The Journal of Neuroscience, 2010Co-Authors: Janna Merte, Alex L. Kolodkin, Qiang Wang, Craig Vander W Kooi, Sarah Sarsfield, Daniel J Leahy, David D. GintyAbstract:We have performed a three-generation, forward genetic screen to identify recessive mutations that affect the patterning of the peripheral nervous system. Using this assay, we identified Sema3AK108N , a novel loss-of-function allele of Sema3A . Class 3 Semaphorins, which include Sema3A, are structurally conserved secreted proteins that play critical roles in the development and function of the nervous system. Sema3AK108N mutant mice phenocopy Sema3A -null mice, and Sema3AK108N protein fails to repel or collapse DRG axons in vitro . K108 is conserved among Semaphorins, yet the loss-of-function effects associated with K108N are not the result of impaired expression, secretion, or binding of Sema3A to its high-affinity receptor Neuropilin-1 (Npn-1). Using in silico modeling and mutagenesis of other Semaphorin family members, we predict that Sema3AK108N interacts poorly with the Npn-1/PlexA holoreceptor and, thus, interferes with its ability to signal at the growth cone. Therefore, through the use of a forward-genetic screen we have identified a novel allele of Sema3A that provides structural insight into the mechanism of Sema3A/Npn-1/PlexinA signaling.
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drosophila plexin b is a sema 2a receptor required for axon guidance
Development, 2006Co-Authors: Joseph C Ayoob, Jonathan R. Terman, Alex L. KolodkinAbstract:Plexin receptors play a crucial role in the transduction of axonal guidance events elicited by Semaphorin proteins. In Drosophila, Plexin A (PlexA) is a receptor for the transmembrane Semaphorin Semaphorin-1a (Sema-1a) and is required for motor and central nervous system (CNS) axon guidance in the developing embryonic nervous system. However, it remains unknown how PlexB functions during neural development and which ligands serve to activate this receptor. Here, we show that plexB, like plexA, is robustly expressed in the developing CNS and is required for motor and CNS axon pathfinding. PlexB and PlexA serve both distinct and shared neuronal guidance functions. We observe a physical association between these two plexin receptors in vivo and find that they can utilize common downstream signaling mechanisms. PlexB does not directly bind to the cytosolic Semaphorin signaling component MICAL (molecule that interacts with CasL), but requires MICAL for certain axonal guidance functions. Ligand binding and genetic analyses demonstrate that PlexB is a receptor for the secreted Semaphorin Sema-2a, suggesting that secreted and transmembrane Semaphorins in Drosophila use PlexB and PlexA, respectively, for axon pathfinding during neural development. These results establish roles for PlexB in central and peripheral axon pathfinding, define a functional ligand for PlexB, and implicate common signaling events in plexin-mediated axonal guidance.
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Semaphorin 7a promotes axon outgrowth through integrins and mapks
Nature, 2003Co-Authors: Jeroen R Pasterkamp, Melanie K Spriggs, Jacques J Peschon, Alex L. KolodkinAbstract:Striking parallels exist between immune and nervous system cellular signalling mechanisms. Molecules originally shown to be critical for immune responses also serve neuronal functions, and similarly neural guidance cues can modulate immune function. We show here that Semaphorin 7A (Sema7A), a membrane-anchored member of the Semaphorin family of guidance proteins previously known for its immunomodulatory effects, can also mediate neuronal functions. Unlike many other Semaphorins, which act as repulsive guidance cues, Sema7A enhances central and peripheral axon growth and is required for proper axon tract formation during embryonic development. Unexpectedly, Sema7A enhancement of axon outgrowth requires integrin receptors and activation of MAPK signalling pathways. These findings define a previously unknown biological function for Semaphorins, identify an unexpected role for integrins and integrin-dependent intracellular signalling in mediating Semaphorin responses, and provide a framework for understanding and interfering with Sema7A function in both immune and nervous systems.
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Neuropilin-2 Is a Receptor for Semaphorin IV Insight into the Structural Basis of Receptor Function and Specificity
Neuron, 1998Co-Authors: Roman J. Giger, Erica Rowe Urquhart, Susan K.h Gillespie, Dorothy V. Levengood, David D. Ginty, Alex L. KolodkinAbstract:Neuropilins bind secreted members of the Semaphorin family of proteins. Neuropilin-1 is a receptor for Sema III. Here, we show that neuropilin-2 is a receptor for the secreted Semaphorin Sema IV and acts selectively to mediate repulsive guidance events in discrete populations of neurons. neuropilin-2 and semaIV are expressed in strikingly complementary patterns during neurodevelopment. The extracellular complement-binding (CUB) and coagulation factor domains of neuropilin-2 confer specificity to the Sema IV repulsive response, and these domains of neuropilin-1 are necessary and sufficient for binding of the Sema III Semaphorin (sema) domain. The coagulation factor domains alone are necessary and sufficient for binding of the Sema III immunoglobulin- (Ig-) basic domain and the unrelated ligand, vascular endothelial growth factor (VEGF). Lastly, neuropilin-1 can homomultimerize and form heteromultimers with neuropilin-2. These results provide insight into how interactions between neuropilins and secreted Semaphorins function to coordinate repulsive axon guidance during neurodevelopment.
