Showing papers on "Neuropilins published in 2006"
TL;DR: The knowledge accumulated since the discovery of these proteins more than 20 years ago is summarized with the emphasis on the signaling pathways activated by VEGF receptors in endothelial cells during cell migration, growth and differentiation.
Abstract: Vascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development and homeostasis but also have profound effects on neural cells. VEGFs are predominantly produced by endothelial, hematopoietic and stromal cells in response to hypoxia and upon stimulation with growth factors such as transforming growth factors, interleukins or platelet-derived growth factor. VEGFs bind to three variants of type III receptor tyrosine kinases, VEGF receptor 1, 2 and 3. Each VEGF isoform binds to a particular subset of these receptors giving rise to the formation of receptor homo- and heterodimers that activate discrete signaling pathways. Signal specificity of VEGF receptors is further modulated upon recruitment of coreceptors, such as neuropilins, heparan sulfate, integrins or cadherins. Here we summarize the knowledge accumulated since the discovery of these proteins more than 20 years ago with the emphasis on the signaling pathways activated by VEGF receptors in endothelial cells during cell migration, growth and differentiation.
370 citations
TL;DR: Neuropilins are multifunctional non-tyrosine kinase receptors that bind to class 3 semaphorins and vascular endothelial growth factor and have been found to play key roles in mediating axonal guidance in the developing nervous system as mentioned in this paper.
Abstract: Neuropilins are multifunctional non-tyrosine kinase receptors that bind to class 3 semaphorins and vascular endothelial growth factor. NRP-1 and NRP-2 were first identified for their key role in mediating axonal guidance in the developing nervous system through their interactions with class 3 semaphorins. Growing evidence supports a critical role for these receptors in tumor progression. Neuropilin expression is up-regulated in multiple tumor types, and correlates with tumor progression and prognosis in specific tumors. Neuropilins may indirectly mediate effects on tumor progression by affecting angiogenesis or directly through effects on tumor cells. This article reviews emerging evidence for the role of neuropilins in tumor biology. The therapeutic implications of these data are far-reaching and suggest that neuropilin-targeted interventions may be useful as a component of antineoplastic therapy.
262 citations
TL;DR: The role of NRPs and SEMAs in tumor progression and angiogenesis is focused on and SEMA3F, which binds specifically to NRP2, inhibits tumor angiogenic and metastasis and may have therapeutic potential.
258 citations
TL;DR: It is shown that plexin-A1 associates with the triggering receptor expressed on myeloid cells-2 (Trem-2), linking semaphorin-signalling to the immuno-receptor tyrosine-based activation motif (ITAM)-bearing adaptor protein, DAP12, that presents a novel signalling mechanism for exerting the pleiotropic functions of semaphors.
Abstract: Semaphorins and their receptors have diverse functions in axon guidance, organogenesis, vascularization and/or angiogenesis, oncogenesis and regulation of immune responses1,2,3,4,5,6,7,8,9,10,11. The primary receptors for semaphorins are members of the plexin family2,12,13,14. In particular, plexin-A1, together with ligand-binding neuropilins, transduces repulsive axon guidance signals for soluble class III semaphorins15, whereas plexin-A1 has multiple functions in chick cardiogenesis as a receptor for the transmembrane semaphorin, Sema6D, independent of neuropilins16. Additionally, plexin-A1 has been implicated in dendritic cell function in the immune system17. However, the role of plexin-A1 in vivo, and the mechanisms underlying its pleiotropic functions, remain unclear. Here, we generated plexin-A1-deficient (plexin-A1−/−) mice and identified its important roles, not only in immune responses, but also in bone homeostasis. Furthermore, we show that plexin-A1 associates with the triggering receptor expressed on myeloid cells-2 (Trem-2), linking semaphorin-signalling to the immuno-receptor tyrosine-based activation motif (ITAM)-bearing adaptor protein, DAP12. These findings reveal an unexpected role for plexin-A1 and present a novel signalling mechanism for exerting the pleiotropic functions of semaphorins.
252 citations
TL;DR: The molecular and functional diversity of VEGF family proteins play multiple physiological roles, such as angiogenesis and lymphangiogenesis, while exogenous members (viral and snake venom VEGFs) display activities that are unique in physiology and function.
Abstract: Members of the vascular endothelial growth factor (VEGF) family are crucial regulators of neovascularization and are classified as cystine knot growth factors that specifically bind cellular receptor tyrosine kinases VEGFR-1, VEGFR-2, and VEGFR-3 with high but variable affinity and selectivity. The VEGF family has recently been expanded and currently comprises seven members: VEGF-A, VEGF-B, placenta growth factor (PlGF), VEGF-C, VEGF-D, viral VEGF (also known as VEGF-E), and snake venom VEGF (also known as VEGF-F). Although all members are structurally homologous, there is molecular diversity among the subtypes, and several isoforms, such as VEGF-A, VEGF-B, and PlGF, are generated by alternative exon splicing. These splicing isoforms exhibit differing properties, particularly in binding to co-receptor neuropilins and heparin. VEGF family proteins play multiple physiological roles, such as angiogenesis and lymphangiogenesis, while exogenous members (viral and snake venom VEGFs) display activities that are unique in physiology and function. This review will highlight the molecular and functional diversity of VEGF family proteins.
232 citations
TL;DR: Findings indicate that the neuropilins and their associated plexin and tyrosine-kinase VEGF receptors play a regulatory role in developmentalAngiogenesis as well as in tumor angiogenesis.
147 citations
TL;DR: The genetic and in vitro evidence implicating four families of ligand-receptor signalling systems common to both neuronal and vessel guidance: the Ephrins and Eph receptors; Semaphorins, Neuropilins and Plexin receptors; Netrin and Unc5 receptors; and Slits and Robo receptors are reviewed.
119 citations
TL;DR: The results suggest that the expression of VEGFRs and NRPs on keratinocytes may constitute important regulators for its activity and may possibly be responsible for the autocrine signaling in the epidermis.
Abstract: Vascular endothelial growth factor (VEGF) plays an important role in normal and pathological angiogenesis. VEGF receptors (VEGFRs, including VEGFR-1, VEGFR-2, and VEGFR-3) and neuropilins (NRPs, including NRP-1 and NRP-2) are high-affinity receptors for VEGF and are typically considered to be specific for endothelial cells. Here we showed expression of VEGFRs and NRPs on cultured epidermal keratinocytes at both mRNA and protein levels. We further localized these receptors by immunofluorescence (IF) staining in the epidermis of surgical skin specimens. We found positive staining for VEGFRs and NRPs in all layers of the epidermis except for the stratum corneum. VEGFR-1 and VEGFR-2 are primarily expressed on the cytoplasmic membrane of basal cells and the adjacent spinosum keratinocytes. All layers of the epidermis except for the horny cell layer demonstrated a uniform pattern of VEGFR-3, NRP-1, and NRP-2. Sections staining for NRP-1 and NRP-2 also showed diffuse intense fluorescence and were localized to the cell membrane and cytoplasm of keratinocytes. In another panel of experiments, keratinocytes were treated with different concentrations of VEGF, with or without VEGFR-2 neutralizing antibody in culture. VEGF enhanced the proliferation and migration of keratinocytes, and these effects were partially inhibited by pretreatment with VEGFR-2 neutralizing antibody. Adhesion of keratinocytes to type IV collagen-coated culture plates was decreased by VEGF treatment, but this reduction could be completely reversed by pretreatment with VEGFR-2 neutralizing antibody. Taken together, our results suggest that the expression of VEGFRs and NRPs on keratinocytes may constitute important regulators for its activity and may possibly be responsible for the autocrine signaling in the epidermis.
109 citations
TL;DR: In this article, the authors examined the expression of class 3 semaphorins (3A, 3B, 3C, 3D, 3E, and 3F) and their receptors (neuropilins 1 and 2, plexins A1, A2, A3, B2, and D1) in undifferentiated and differentiated mouse podocytes using reverse transcriptase-polymerase chain reaction (RT-PCR).
77 citations
TL;DR: In this article, the authors assessed expression patterns of angiogenesis-related genes in mouse retina during perinatal vascularization and in adulthood, and found that vascular endothelial growth factor (vegf) and its receptors flk, flt1, and neuropilins 1 and 2 are expressed in both vascularized and avascular areas.
52 citations
TL;DR: The in situ hybridization study revealed that the expression patterns of plexins and neuropilins are only partially overlapping, especially during early and intermediate stages of spinal cord development, supporting both cooperative and separate functions of pLexin and neuroPilins in neural circuit formation.
Abstract: Plexins are a family of transmembrane proteins that were shown to act as receptors for Semaphorins either alone or in a complex together with Neuropilins. Based on structural criteria Plexins were subdivided into 4 classes, A through D. PlexinAs are mainly thought to act as mediators of repulsive signals in cell migration and axon guidance. Their functional role in vertebrates has been studied almost exclusively in the context of Semaphorin signaling, i.e. as co-receptors for class 3 Semaphorins. Much less is known about Plexins of the other three classes. Despite the fact that Plexins are involved in the formation of neuronal circuits, the temporal changes of their expression patterns during development of the nervous system have not been analyzed in detail. Only seven plexins are found in the chicken genome in contrast to mammals, where nine plexins have been identified. Here, we describe the dynamic expression patterns of all known plexin family members in comparison to the neuropilins in the developing chicken spinal cord. Our in situ hybridization study revealed that the expression patterns of plexins and neuropilins are only partially overlapping, especially during early and intermediate stages of spinal cord development, supporting both cooperative and separate functions of plexins and neuropilins in neural circuit formation.
TL;DR: A novel method of isolating TEB and ducts free of stroma was developed, and the gene expression profiles of these two isolates were compared using oligonucleotide microarrays, suggesting that these genes may influence ductal growth and morphogenesis in the developing mammary gland.
Abstract: Mammary morphogenesis in the mouse is driven by specialized structures at the ends of the developing ducts, the terminal end buds (TEB). The mechanisms controlling the precise branching and spacing of the ducts are, as yet, unknown. To identify genes that are associated with migration of TEB and differentiation of the subtending ducts, we developed a novel method of isolating TEB and ducts free of stroma, and compared the gene expression profiles of these two isolates using oligonucleotide microarrays. Ninety one genes were upregulated in TEB compared to ducts. Three of these genes, Sprr1A, Sema3B, and BASP1, are associated with axonal growth and guidance. Two additional members of the Sprr family, Sprr2A and 2B, not previously associated with axonal growth, were also highly expressed in TEB. Expression of these genes was confirmed by RT-PCR and Western blotting, and the cellular distribution of Sprr1A and BASP1 was demonstrated by immunohistochemistry. Other semaphorins, including Sema3C, 4A, 4F and the cancer invasion associated Sema 4D were also expressed in the mouse mammary gland along with the semaphorin receptors, Plexins A2, A3, B2, and D1, and Neuropilins 1 and 2. These results are discussed in the context of other proteins expressed in the developing gland that are known to be downstream effectors of these signaling molecules. We suggest that these genes may influence ductal growth and morphogenesis in the developing mammary gland.
TL;DR: The findings that RPE cells produce and respond to PlGF indicate that the factor exerts an autocrine/paracrine action on these cells, and it is suggested that increased expression of TGF-β-related growth factors during diabetic retinopathy may cause PlGF secretion by R PE cells contributing to the stimulation of cell migration as a critical component of the progression of fibrovascular membranes.
Abstract: Background
Placenta growth factor (PlGF) is an important co-factor in retinal neovascularization. To examine whether retinal pigment epithelial (RPE) cells may represent a source for PlGF during retinopathy, we determined whether human RPE cells in vitro produce and respond to PlGF. In addition, we determined whether the cells express receptors for PlGF, i.e. flt-1 and neuropilins.
TL;DR: This chapter describes the optimization of this assay and outlines the subtle differences required to enable Sema3A-Fc and Sema4D-fc to induce identical collapse phenotypes in COS cells expressing Plexin-A1 and neuropilin-1, orPlexin-B1, respectively.
Abstract: Semaphorins are a family of growth cone guidance molecules. When associated with their receptors and coreceptors, plexins and neuropilins, they act as chemorepellents for an extensive range of neuronal populations. The prototypic semaphorin, Sema3A, has a potent inhibitory effect on sensory axons emanating from dorsal root ganglia. This has formed the basis of the most famous assay for semaphorin activity, the chick dorsal root ganglia collapse assay. Recently, a heterologous, highly tractable assay has been used to investigate semaphorin signaling. In this system, the binding of recombinant semaphorins to COS cells expressing plexins and neuropilins induces a morphological collapse that may correlate with growth cone collapse. This chapter describes the optimization of this assay and outlines the subtle differences required to enable Sema3A-Fc and Sema4D-Fc to induce identical collapse phenotypes in COS cells expressing Plexin-A1 and neuropilin-1, or Plexin-B1, respectively.
TL;DR: Comparison of the expression patterns of the class III semaphorins 3A, 3C, and 3F and neuropilins 1 and 2 between mouse and chick embryos at early developmental stages showed large similarities, but important differences were also detected.
15 Aug 2006
TL;DR: Vascular Endothelial Growth Factor: Pathophysiology and Clinical Implications, N.A. Shawber and J.J. Ferrara Signal Transduction of VEGF Receptors toward Angiogenesis, M.I. Haiko and A. Shaked Using an Anti-VEGF Monoclonal Antibody to Treat Cancer.
Abstract: Vascular Endothelial Growth Factor: Pathophysiology and Clinical Implications, N. Ferrara Signal Transduction of VEGF Receptors toward Angiogenesis, M. Shibuya Growth Factors and Lymphangiogenesis, P.I. Haiko, M.J. Karkkainen, M.G. Achen, S.A. Stacker, and K. Alitalo Notch and Vascular Development, C.J. Shawber and J. Kitajewski Neural Guidance Molecules in Vascular Development, L. Yuan, P. Corvol, and A. Eichmann Neuropilins, Receptors for the VEGF and Semaphorin Families, Link Angiogenesis and Axon Guidance, P. Kurschat, D. Bielenberg, and M. Klagsbrun Non-Angiogenic Functions of VEGF, J.J. Haigh, C. Ruiz de Almodovar, M. Schneider, and P. Carmeliet Contribution of Pro-Angiogenic Hematopoietic Cells to Vascularization of Tumor and Ischemic Tissue, S. Rafii, D. Lyden, D. Jin, and A. Hooper Selected Antiangiogenic Drugs as Potentially Effective Universal Chemosensitizers, R.S. Kerbel, F. Bertolini, S. Man, D.J. Hicklin, U. Emmenegger, and Y. Shaked Using an Anti-VEGF Monoclonal Antibody to Treat Cancer, Z.A. Wainberg and F. Kabbinavar Ocular Neovascularization, P.A. Campochiaro Targeting VEGF for Neovascular Age-Related Macular Degeneration and Macular Edema, P.J. Rosenfeld and A.E. Fung Therapeutic Angiogenesis for Cardiovascular Disease, R. Khurana and M. Simons
Patent•
28 Jun 2006TL;DR: In this paper, a peptidic antagonist of class III semaphorins/neuropilins complexes comprising an amino acid sequence, which is derived from the transmembrane domain of a protein selected in the group consisting of neuropilin-1, neuropilsin-2, plexin-Al, plexinsin-A2, Plexins-A3,Plexin A4, Nr-CAM, Ll-CAMP, integrin Beta 1 and integrin beta 2, and including at least a G
Abstract: The present invention concern a peptidic antagonist of class III semaphorins/neuropilins complexes comprising an amino acid sequence, which is derived from the transmembrane domain of a protein selected in the group consisting of neuropilin-1, neuropilin-2 , plexin-Al, plexin-A2, plexin-A3, plexin-A4, Nr-CAM, Ll-CAM, integrin Beta 1 and integrin beta 2, and including at least a GxxxG motif, eventually fused to an heterologous sequence; a nucleic acid encoding for said peptidic antagonist, a pharmaceutical composition comprising such a peptidic antagonist or a nucleic acid encoding thereof and uses thereof .
01 Jan 2006
TL;DR: Vascular endothelial growth factor (VEGF or VEGF-A) is the prototype and best-described member of a family of at least six largely endothelial-specific, heparin-binding, angiogenic growth factors.
Abstract: Vascular endothelial growth factor (VEGF or VEGF-A) is the prototype and best-described member of a family of at least six largely endothelial-specific, heparin-binding, angiogenic growth factors. VEGF family members are crucial to the normal development and maintenance of the vascular and lymphatic systems. VEGF stimulates endothelial cells to degrade extracellular matrix, proliferate, migrate, and form tubes, and acts as an endothelial cell survival factor. VEGF also increases vascular permeability, leading to its alternative name, vascular permeability factor. VEGF family members exert their effects through interactions with a family of three VEGF receptors and with two co-receptors known as neuropilins. Differing combinations of VEGF family members and receptors mediate tissue-specific effects. Expression of VEGF in the developing pulmonary epithelium is a major modulator of normal pulmonary vascular development during fetal life. Following a number of pulmonary insults, both local increases in VEGF production, which result in increased vascular leakage and edema, and an overall decrease in VEGF abundance, which coincides with microvascular endothelial cell loss, are associated with the development of acute lung injury. VEGF production by lung cancers is an important mechanism by which the cancers recruit new vasculature, allowing them to grow, invade neighboring tissue, and metastasize.
15 Aug 2006