Showing papers on "Neuropilins published in 2002"
TL;DR: Gene targeting experiments indicate that np1 does indeed function as an important modulator of VEGF function during vasculogenesis and angiogenesis, but the role of np2 in the cardiovascular system has not been studied in detail as yet.
354 citations
TL;DR: It is observed that in fyn- and cdk5-deficient mice, Sema3A-induced growth cone collapse responses were attenuated compared to their heterologous controls, and a signal transduction pathway in which Fyn and Cdk5 mediate neuronal guidance regulated by Sema 3A is proposed.
350 citations
TL;DR: The identity of contact sites between Npn-1 and its semaphorin ligands are established, and they provide a foundation for understanding how NPN-1 functions as a receptor for distinct classes of ligands in vivo.
237 citations
TL;DR: It was recently reported by two laboratories that Neuropilins can form complexes with the second tyrosine-kinase receptor of VEGF, VEGFR1, however, the biological function of these complexes is still unclear.
Abstract: The Neuropilin-1 (NRP 1) and Neuropilin-2 (NRP2) receptors were initially described as receptors for axon guidance factors belonging to the class-3 Semaphorin sub-family. Subsequently, it was found the Neuropilins also function as receptors for some forms of vascular endothelial growth factor (VEGF). VEGF165 binds to both NRP 1 and to NRP2 but VEGF121 does not bind to either of these receptors. VEGF145 on the other hand, binds to NRP2 but not to NRP1. Additional VEGF family members such as the heparin binding form of placenta growth factor (PIGF2) and VEGF-B bind to NRP 1, and it was also shown that both PIGF-2 and VEGFC bind to NRP2.
166 citations
TL;DR: This review uses the semaphorin proteins, which were first identified as repellents for navigating axons, as an example to illustrate the principles learned in the molecular mechanisms of axon guidance and other processes of neuronal development.
Abstract: Neuronal connections are made during embryonic development with astonishing precision to ultimately form the physical basis for the central nervous system's main capacity: information processing. Over the past few decades, much has been learned about the general principles of axon guidance. A key finding to emerge is that extracellular cues play decisive roles in establishing the connections. One family of such cues, the semaphorin proteins, was first identified as repellents for navigating axons during brain wiring. Recent studies have implicated these molecules in many other processes of neuronal development, including axonal fasciculation, target selection, neuronal migration, and dendritic guidance, as well as in the remodeling and repair of the adult nervous system. It appears that responding neuronal processes sense these semaphorin signals by a family of transmembrane molecules, namely the plexins, even though neuropilins were also found to be required for mediating the interaction between plexins and class 3 semaphorins. Our understanding of the intracellular signaling machinery linking the receptors to the cytoskeleton machinery is still incomplete, but several molecules have been implicated in mediating or modulating semaphorin-induced responses. Adding to the complexity of semaphorin biology, new findings implicate semaphorins in functioning not only as signaling ligands, but also as signal-transducing receptors. Thus, semaphorins may serve as important probes for exploring the mechanisms of intercellular communication during the development and function of the nervous system.
144 citations
Journal Article•
TL;DR: Roles of neuropilins in driving axon fasciculation, channeling various axonal populations, inhibiting axonal branching, creating exclusion zones for axons, and providing directional guidance cues by being presented in gradients are summarized.
Abstract: After the initial discovery of neuropilin-1 as an epitope on axons recognized by a monoclonal antibody, neuropilins were rediscovered in the search for receptors mediating the repulsive actions of class 3 Semaphorins, notably Sema3A. Neuropilins are the ligand binding moieties in the class 3 Semaphorin receptor complexes, with the signaling moieties apparently provided by members of the plexin family. In their capacity as Semaphorin receptors, neuropilins have been shown to transduce repulsive guidance signals that direct a large variety of cell migration and axon guidance events. We summarize their demonstrated roles in driving axon fasciculation, channeling various axonal populations, inhibiting axonal branching, creating exclusion zones for axons, and providing directional guidance cues by being presented in gradients. In addition to their roles in repulsive axon guidance, evidence is accumulating that neuropilins also transduce some attractive guidance functions of Semaphorins.
128 citations
TL;DR: The results suggest a shift in the balance between semaphorins and VEGF/PLGF, which compete for NP-binding, thus inducing angiogenesis and suggesting a neurotrophic/neuroprotective role of V EGF/ PLGF.
Abstract: Neuropilin-1 and -2 (NP-1/NP-2) are transmembrane receptors that play a role in axonal guidance by binding of class III semaphorins, and in angiogenesis by binding of the vascular endothelial growth factor isoform VEGF165 and placenta growth factor (PLGF). We investigated the expression pattern of NP-1/NP-2, their co-receptors, vascular endothelial growth factor receptor-1 and -2 (VEGFR-1, VEGFR-2), and their ligands, class III semaphorins, VEGF and PLGF, following experimental cerebral ischemia in mice. By means of in situ hybridization and immunohistochemistry we observed loss of expression of class III semaphorins in neurons in the infarct/peri-infarct area. In contrast, we observed high expression of NP-1 in vessels, neurons, and astrocytes surrounding the infarct. VEGF and PLGF were upregulated in different cell types following stroke. Our results suggest a shift in the balance between semaphorins and VEGF/PLGF, which compete for NP-binding. Possibly, the loss of semaphorins facilitates binding of the competing ligands (VEGF/PLGF), thus inducing angiogenesis. In addition, the observed expression patterns further suggest a neurotrophic/neuroprotective role of VEGF/PLGF.
103 citations
01 Jan 2002
TL;DR: Roles of neuropilins in driving axon fasciculation, channeling various axonal populations, inhibiting axonal branching, creating exclusion zones for axons, and providing directional guidance cues by being presented in gradients are summarized.
Abstract: After the initial discovery of neuropilin-1 as an epitope on axons recognized by a monoclonal antibody, neuropilins were rediscovered in the search for receptors mediating the repulsive actions of class 3 Semaphorins, notably Sema3A. Neuropilins are the ligand binding moieties in the class 3 Semaphorin receptor complexes, with the signaling moieties apparently provided by members of the plexin family. In their capacity as Semaphorin receptors, neuropilins have been shown to transduce repulsive guidance signals that direct a large variety of cell migration and axon guidance events. We summarize their demonstrated roles in driving axon fasciculation, channeling various axonal populations, inhibiting axonal branching, creating exclusion zones for axons, and providing directional guidance cues by being presented in gradients. In addition to their roles in repulsive axon guidance, evidence is accumulating that neuropilins also transduce some attractive guidance functions of Semaphorins.
93 citations
TL;DR: Cross talk between Semaphorin and VEGF on neuropilin suggests that class 3 semaphorins and the secreted forms of neuro pilin act as antagonists to V EGF and its related growth factors.
Abstract: Neuropilin is a type I transmembrane protein and the molecular mass is 120 kDa Two homologues, Neuropilin-1 and -2, are identified The primary structure of Neuropilin-1 and Neuropilin-2 is well conserved and is divided into four domains, CUB (a1/a2) domain, FV/FVIII (b1/62) domain, MAM (c) domain, and (d) domain that contains a transmembrane and a short cytoplasmic region Both Neuropilin-1 and Neuropilin-2 have truncated and secreted form of splice variants Neuropilins act as a receptor for two different extracellular ligands, class 3 semaphorins and specific isoforms of vascular endothelial growth factor In both cases, neuropilin requires an additional transmembrane molecule to exhibit biological activity PlexinA is essential for class 3 semaphorin signaling Vascular endothelial cell growth factor (VEGF) receptor is the major receptor for VEGF and neuropilin acts as isoform specific co-receptor for VEGF The CUB and FV/FVIII domains of Neuropilin are the binding sites of semaphorin and VEGF The MAM domain mediates semaphorin signaling to Plexin-A Cross talk between semaphorin and VEGF on neuropilin suggests that class 3 semaphorins and the secreted forms of neuropilin act as antagonists to VEGF and its related growth factors
85 citations
TL;DR: Observations suggest that the injury induced regulation of Semaphorin 3A in the PNS contributes to successful regeneration and target reinnervation.
Abstract: Injury to the mature mammalian central nervous system (CNS) is often accompanied by permanent loss of function of the damaged neural circuits. The failure of injured CNS axons to regenerate is thought to be caused, in part, by neurite outgrowth inhibitory factors expressed in and around the lesion. These include several myelin associated inhibitors, proteoglycans, and tenascin-R. Recent studies have documented the presence of class 3 semaphorins in fibroblast-like meningeal cells present in the core of the neural scar formed following CNS injury. Class 3 semaphorins display neurite growth-inhibitory effects on growing axons during embryonic development. The induction of the expression of class 3 semaphorins in the neural scar and the persistent expression of their receptors, the neuropilins and plexins, by injured CNS neurons suggest that they contribute to the regenerative failure of CNS neurons. Neuropilins are also expressed in the neural scar in a subpopulation of meningeal fibroblast and in neurons in the vicinity of the scar. Semaphorin/neuropilin signaling might therefore also be important for cell migration, angiogenis and neuronal cell death in or around neural scars. In contrast to neurons in the CNS, neuropilin/plexin positive neurons in the PNS do display long distance regeneration following injury. Injured PNS neurons do not encounter a semaphorin positive neural scar. Furthermore, Semaphorin 3A is downregulated in the regenerating spinal motor neurons themselves. This was accompanied by a transient upregulation of Semaphorin 3A in the target muscle. These observations suggest that the injury induced regulation of Semaphorin 3A in the PNS contributes to successful regeneration and target reinnervation. Future studies in genetically modified mice should provide more insight into the mechanisms by which neuropilins and semaphorins influence nervous system regeneration and degeneration.
72 citations
TL;DR: In this article, the authors describe the isolation and detailed characterizations of a novel gene, named CLCP1, which corresponds to one of such expression sequence tags with up-regulated expression in LNM35.
Abstract: Most lung cancer patients are unfortunately uncurable and die because of widespread metastases, thus indicating the importance of identification of molecules with a crucial role in this process. Our previous expression profiling analysis of a highly metastatic lung cancer cell line, NCI-H460-LNM35, and its parental low metastatic line, NCI-H460-N15, revealed significant up-regulation of both known and unknown genes in LNM35. In this study, we describe the isolation and detailed characterizations of a novel gene, named CLCP1, which corresponds to one of such expression sequence tags with up-regulated expression in LNM35. The CLCP1 gene was found to encode a protein with 775 amino acids with structural similarities to, but distinct from neuropilins, cell surface receptors for VEGF165 and semaphorins. Notably, CLCP1 was shown to be up-regulated not only in LNM35 in association with its acquisition of metastatic phenotype during in vivo selection, but also in a significant fraction of lung cancers in vivo with high frequency in metastatic lesions, warranting future studies for a better understanding of the molecular mechanisms of lung cancer metastasis.
TL;DR: The sum of the guidance cues provided by VEGF and semaphorins 3A and 3F may be important determinants of the pattern of endothelial cell migration during kidney morphogenesis.
TL;DR: In this receptor complex neuropilins act as the ligand-binding subunit while plexins function as the signal-transducing subunit in the induction of cytoskeletal collapse by semaphorins.
Abstract: Neuropilins bind the secreted class 3 semaphorins with high affinity but require a member of the plexin family to form receptors that are able to activate downstream signal transduction cascades. In this receptor complex neuropilins act as the ligand-binding subunit while plexins function as the signal-transducing subunit in the induction of cytoskeletal collapse by semaphorins. The cytoplasmic domain is highly conserved within the plexin family and interacts with Rho-like GTPases.
Patent•
25 Jul 2002
TL;DR: In this article, it is hypothesized that T2-TrpRS acts as a competitive antagonist of VEGF-neuropilin interaction with consequent disruption of angiogenesis.
Abstract: The vascular endothelial cell growth factor receptor, neuropilin, is a selective binding partner for the anti-angiogenic molecule T2-TrpRS. This binding inhibits VEGF-mediated activity by effectively blocking VEGF binding to neuropilin. It is hypothesized that T2- TrpRS acts as a competitive antagonist of VEGF-neuropilin interaction with consequent disruption of angiogenesis. This discovery is exploited to provide novel methods for the treatment of diseases and conditions impacted by T2- TrpRS or T2- TrpRS derivatives via their interaction with neuropilins.
TL;DR: The sum of the guidance cues provided by VEGF and semaphorins 3A and 3F may be important determinants of the pattern of endothelial cell migration during kidney morphogenesis.
TL;DR: Neuropilins are receptors for class 3 Semaphorins and function as co-receptors for Vascular endothelial growth factor isoforms, VEGF165 and V EGF145 and related molecules and appear to be mutually antagonistic.
Abstract: Neuropilins (NRPs) are receptors for class 3 Semaphorins and function as co-receptors for Vascular endothelial growth factor isoforms, VEGF165 and VEGF145 and related molecules. NRPs are expressed in a variety of neural and non-neural tissues and are required for normal development. Interestingly, class 3 Semaphorins and VEGF compete for common NRP binding. As a consequence, Semaphorins and VEGF appear to be mutually antagonistic. In the lung, NRP levels increase during development and NRPs and Semaphorins are involved in lung branching, probably by altering cell morphology or by regulating cell motility and migration. During lung tumorigenesis, both NRP and VEGF expression increase on dysplastic lung epithelial cells; SEMA3F expression is reduced and SEMA3F protein is delocalized from the membrane to the cytoplasm. In lung cancers, SEMA3F staining correlates inversely with tumor stage with high SEMA3F associated with less aggressive tumors. Conversely, more aggressive tumors are associated with increased VEGF staining and a corresponding loss in membranous SEMA3F.
Journal Article•
Book•
01 Jan 2002
TL;DR: The role of neuropilin in vascular and tumor biology and in vivo functions in neuronal cell migration and axon guidance, and its ligands in normal lung and cancer.
Abstract: 1: From the discovery of neuropilin to the determination of its adhesion sites H. Fujisawa. 2: Neuropilins as semaphorin receptors: in vivo functions in neuronal cell migration and axon guidance A. Bagri, M. Tessier-Lavigne. 3: The role of neuropilin in vascular and tumor biology M. Klagsbrun, S. Takashima, R. Mamluk. 4: Neuropilin-1 in the immune system P.-H. Romeo, V. Lemarchandel, R. Tordjman. 5: Structural and functional relation of neuropilins F. Nakamura, Y. Goshima. 6: The function of neuropilin/plexin complexes A.W. Puschel. 7: The interaction of neuropilin-1 and neuropilin-2 with tyrosine-kinase receptors for VEGF G. Neufeld, O. Kessler, Y. Herzog. 8: The function of neuropilin / L1 complex V. Castellani. 9: Neuropilin and its ligands in normal lung and cancer J. Roche, H. Drabkin, E. Brambilla. 10: Neuropilin and class 3 semaphorins in nervous system regeneration F. de Winter, A.J.G.D. Holtmaat, J. Verhaagen. Index.
TL;DR: The scenario proposed here for OTK function is that OTK associates with plexins on the axon surface (although this remains to be demonstrated) and operates downstream of the Semaphorins to transduce signals.