Showing papers on "Neuropilins published in 2017"

Multifaceted Role of Neuropilins in the Immune System: Potential Targets for Immunotherapy.

Abstract: Neuropilins (NRPs) are non-tyrosine kinase cell surface glycoproteins expressed in all vertebrates and widely conserved across species. The two isoforms, such as neuropilin-1 (NRP1) and neuropilin-2 (NRP2), mainly act as coreceptors for class III Semaphorins and for members of the vascular endothelial growth factor family of molecules and are widely known for their role in a wide array of physiological processes, such as cardiovascular, neuronal development and patterning, angiogenesis, lymphangiogenesis, as well as various clinical disorders. Intriguingly, additional roles for NRPs occur with myeloid and lymphoid cells, in normal physiological as well as different pathological conditions, including cancer, immunological disorders, and bone diseases. However, little is known concerning the molecular pathways that govern these functions. In addition, NRP1 expression has been characterized in different immune cellular phenotypes including macrophages, dendritic cells, and T cell subsets, especially regulatory T cell populations. By contrast, the functions of NRP2 in immune cells are less well known. In this review, we briefly summarize the genomic organization, structure, and binding partners of the NRPs and extensively discuss the recent advances in their role and function in different immune cell subsets and their clinical implications.

The neuropilin 2 isoform NRP2b uniquely supports TGFβ-mediated progression in lung cancer

Abstract: Neuropilins are pleiotropic co-receptors for semaphorins and other growth factors, such as TGFβ. In established tumors, TGFβ promotes cell migration and metastasis. Using cell lines, mouse models, and primary patient material, Gemmill et al . found that the roles of the two neuropilin 2 isoforms were distinct in non–small cell lung cancer (NSCLC) cells. Experiments with cultured cells and xenografted tumors with high and low abundance of NRP2a and NRP2b showed that, in contrast to NRP2a, NRP2b inhibited primary tumor growth but mediated TGFβ-induced epithelial-to-mesenchymal transition, cell migration, metastasis, and drug resistance. High amounts of NRP2b in tumors correlated with that of the immunosuppressive ligand PD-L1 and with drug resistance, metastatic disease, and poor prognosis in patients. Selectively targeting this isoform may prevent disease progression and improve drug efficacy in some patients.

Expression of Semaphorins, Neuropilins, VEGF, and Tenascins in Rat and Human Primary Sensory Neurons after a Dorsal Root Injury.

Abstract: Dorsal root injury is a situation not expected to be followed by a strong regenerative growth, or growth of the injured axon into the central nervous system of the spinal cord, if the central axon of the dorsal root is injured but of strong regeneration if subjected to injury to the peripherally projecting axons. The clinical consequence of axonal injury does lead to loss of sensation and may also lead neuropathic pain. In this study we have used in situ hybridization to examine the distribution of mRNAs for the neural guidance molecules semaphorin 3A (SEMA3A), semaphorin 3F(SEMA3F) and semaphorin 4F(SEMA4F), their receptors neuropilin 1 (NP1) and neuropilin 2 (NP2) but also for the neuropilin ligand vascular endothelial growth factor (VEGF) and Tenascin J1, an extracellular matrix molecule involved in axonal guidance, in rat dorsal root ganglia (DRG) after a unilateral dorsal rhizotomy (DRT) or sciatic nerve transection (SNT). The studied survival times were 1-365 days. The different forms of mRNA´s were unevenly distributed between the different size classes of sensory nerve cells. The results show that mRNA for SEMA3A was diminished after trauma to the sensory nerve-roots in rats. The SEMA3A receptor NP1, and SEMA3F receptor NP2, was significantly up regulated in the DRG neurons after DRT and SNT. SEMA4F was up regulated after a SNT. The expression of mRNA for VEGF in DRG neurons after DRT showed a significant up regulation that was high even a year after the injuries. These data suggest a role for the semaphorins, neuropilins, VEGF and J1 in the reactions after dorsal root lesions.

Neuropilins as Signaling Hubs, Controlling Tyrosine Kinases and Other Cell Surface Receptors

Abstract: Neuropilin-1 and neuropilin-2 form a small family of transmembrane molecules found in vertebrates. In addition to their established function as cell surface co-receptors for semaphorins and vascular endothelial growth factors (VEGFs), in association with plexins and VEGF receptors, neuropilins have been found to interact with many other transmembrane receptor molecules (such as EGFR, Met, IGF1-R and PDGF-R tyrosine kinases, TGFb receptor, Hedgehog, integrins, etc.) and elicit a range of intracellular signaling cascades. Thus neuropilins appear to act as signaling hubs on the cell surface, contributing to diverse signaling cascades in response to extracellular cues. Beyond their role in neurovascular embryo development, both neuropilins have been widely implicated in adult functions, especially in cancer. In this context, they are found not only in cancer cells but also in cells of the tumor microenvironment, in particular endothelial cells of tumor vasculature and tumor-associated macrophages. Thus, neuropilin function in cancer is multifaceted, because it implicates diverse receptor signaling complexes in different cell populations. In this chapter, we will mainly focus on the role of neuropilin-1 and neuropilin-2 in the regulation of associated signaling molecules in human tumors, beyond plexins or VEGF receptors.

The Role of Neuropilins in TGF-β Signaling and Cancer Biology

Abstract: The neuropilins (Nrps) interact with a number of growth factors (GFs) and/or their receptors. This includes vascular endothelial growth factor (VEGF), transforming growth factor β1 (TGF-β1), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and epidermal growth factor receptor (EGFR). These interactions can involve one or both homologues, Nrp1 and Nrp2, and generally enhance the response to these GFs. Here, we will review non-VEGF interactions, with emphasis on TGF-β. We found that both Nrp1 and Nrp2 bind active TGF-β1 and its latent form denoted latency associated peptide (LAP)-TGF-β1. The Nrps also bind to the signaling TGF-β receptors (TβRI and TβRII) and the co-receptor betaglycan (TβRIII). Studies by us and others established that Nrp1 and Nrp2 augment TGF-β canonical (Smad2/3-dependent) or noncanonical signaling. This was observed in fibroblasts, hepatic stellate cells, lymphocytes, endothelial cells, cardiomyocytes, and several types of cancer cells. TGF-β1-mediated effects that were reduced by Nrp1 or Nrp2 knockdown and/or enhanced by their overexpression include collagen production, epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndMT), cancer cell activities (e.g., migration and invasion), and regulatory T-cell-mediated suppression. TGF-β markedly upregulated the expression of Nrp2 on cancer cells, which promoted EMT. Conventional CD4+ T lymphocytes induced to express Nrp1 acquired immunosuppressive activity. These effects appear cell type and context dependent, and in some cases Nrps did not enhance or reduced canonical signaling. In conclusion, the Nrps impact on the stimulatory capacity of TGF-β and other GFs, and this is relevant to angiogenesis, wound healing, cancer biology, immunity, and other processes. As such, the Nrps are important targets for drug development.

Guidance molecules and chemokines in angiogenesis and vascular remodeling

Abstract: Apart from major molecules involved in angiogenesis, such as growth factors, cytokines and chemokines, much attention is now being paid to guidance molecules that determine growth trajectories of the de novo formation of blood vessels (ephrins and their receptors, semaphorin receptors neuropilins and plexins, Slit receptor Robo, netrin receptor UNC5B, urokinase and its receptor uPAR, T-cadherin). Guidance receptors play an important role in the regulation of vascular growth trajectory during embryogenesis and vascular regeneration in adults. Besides, matrix metalloproteinases (MMPs) and serine proteases (plasmin and urokinase) are also essential for angiogenesis and vascular wall remodeling. Aberrant gene expression profiles or signaling pathways related to the above proteins can lead to various pathologies.

Using Heterologous COS-7 Cells to Identify Semaphorin-Signaling Components.

Abstract: 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 This heterologous system using COS-7 cells has been developed and widely used to investigate semaphorin-signaling pathways In this chapter, we describe a COS-7 collapse assay protocol used to identify semaphorin-signaling components and a method to produce recombinant class 3 semaphorin proteins

The Role of the Neuropilins in Developmental Angiogenesis

Abstract: The process of angiogenesis, defined as the sprouting of new blood vessels from existing ones, is a key process in the development of the cardiovascular system and is tightly regulated by a plethora of signalling pathways. The transmembrane receptor neuropilin 1 (NRP1) is expressed in blood vascular endothelial cells to regulate angiogenesis by binding to several different ligands and receptors. Here, we provide an overview of the various functions of NRP1 in angiogenesis during both embryonic and postnatal blood vascular development with particular reference to studies that have defined these functions on the cellular and molecular level. We additionally discuss briefly possible roles for the NRP1 homolog NRP2 in vascular development and the requirements for NRP1 and NRP2 in lymphatic vascular development.

Functions of Neuropilins in Wiring the Nervous System and Their Role in Neurological Disorders

Abstract: The proper wiring of the nervous system depends on an orderly series of events, beginning in embryonic development with neuronal migration, axon and dendrite development, and guidance events and continuing in postnatal development with synaptogenesis, pruning of axonal projections, and synapse refinement. In the nervous system, neuropilins function mainly with the class 3 secreted semaphorins (Sema3s) to mediate a majority of these developmental processes. Neuropilins bind to Sema3s as obligatory cell surface co-receptors and form a complex with the type A plexin family members, as well as with cell adhesion molecules and other modulatory co-receptors, to activate intracellular signaling networks that, in most cases, influence cytoskeletal dynamics and neuronal morphology. Changes to neuronal morphology are known to regulate neural connectivity and activity. In this chapter we will focus on recent discoveries of neuropilin functions, mediated by Sema3 signaling, to regulate wiring of the nervous system. In addition, we will highlight some of the emerging roles neuropilins play in neurodevelopmental and neuropsychiatric disorders.

The Role of the Neuropilins in Tumour Angiogenesis and Tumour Progression

Abstract: Neuropilins (NRPs) are multifunctional receptors for class 3 semaphorins, which are responsible for axon guidance during the development of the nervous system in vertebrates, and for vascular endothelial growth factors (VEGFs), essential for vascular development and angiogenesis in disease. There is now a large body of evidence that NRPs also mediate tumour angiogenesis and progression, and they have also emerged as novel therapeutic targets in cancer. Many neoplastic cell types express NRPs, and NRP1 and NRP2 upregulation is positively correlated with tumour progression and poor patient prognosis in several cancer types (Pellet-Many et al. Biochem J 411:211–226, 2008). Recently, NRPs have been shown to play novel roles in the tumour stem cell niche and in regulation of tumour immunity. This chapter focuses on the role of NRPs in tumour angiogenesis and tumour progression, focusing on the role of the NRPs as modulators of VEGF function and highlighting approaches to therapeutic targeting of NRPs in cancer.

Neuropilin 1 and Neuropilin 2: Cancer Progression and Biomarker Analysis

Abstract: Neuropilins (NRP, human; Nrp, mouse) are a family of cell surface protein receptors originally named for their role in neuronal guidance during embryonic development. Over the past two decades, the expression, localization, regulation, and function of the NRP family have been intensely studied. The two-member family composed of neuropilin 1 (NRP1) and neuropilin 2 (NRP2) has now been shown to drive diverse processes including neuronal guidance, vasculogenesis, lymphangiogenesis, immunity, smooth muscle tone, epithelial cell migration and branching, epithelial-to-mesenchymal transition, and cancer progression. Although the two receptors share high sequence homology and domain structure, their unique ligand specificity, co-receptor nature, and disparate cell-specific expression patterns mediate pleiotropic functions in multiple tissue systems. Their abundant expression in a myriad of cancers and their location on the cell surface make them prime targets for antitumor therapies and potential use as surrogate biomarkers.

Crosstalk Between Cell Adhesion Molecules and the Semaphorin/Neuropilin/Plexin Signalling

Abstract: Signalling by cell adhesion molecules (IgCAMs) plays diverse and fundamental roles in the formation, maturation and function of the nervous system. Investigations of their mechanisms of action during early steps of the wiring of neuronal circuits uncovered a contribution of the L1CAM subgroup of IgCAMs in axonal responses to Class 3 Semaphorins (Sema3s), which are secreted in vertebrates. L1CAMs were found to interact with Neuropilins (NRPs), the ligand-binding moiety of Sema3 receptor complexes. As such, L1-NRP cis interactions were shown to be required for some Sema3s to elicit a neuronal guidance response, while trans interactions were found to regulate the nature of the response. From these initial findings, additional contributions and molecular interplay with the Semaphorin signalling have been characterized, which expand the physiological and pathological contexts in which IgCAM/Semaphorin crosstalk might contribute.

Plate-Based Assay for Measuring Direct Semaphorin-Neuropilin Interactions

Abstract: 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 Here we describe an in vitro plate-based binding assay for characterization of the Sema3/Nrp interaction This assay utilizes Nrp-affinity plates and an alkaline phosphatase (AP)-Sema3 fusion to rapidly measure direct Sema3/Nrp binding This assay can be used to measure receptor-ligand binding, the contribution of different domains, and exogenous factors, and to characterize competitive ligand binding

The Roles of Neuropilins in the Immune System

Abstract: Although the neuropilins (Nrps), neuropilin-1 (Nrp1) and its homologue neuropilin-2 (Nrp2), were originally identified as key molecules involved in the development of neurons, it has recently become clear that they also play important roles in the immune system. The function of Nrp1 has been well characterized, mainly in T cells, including regulatory T (Treg) cells, as well as in dendritic cells (DCs), whereas the immunological function of Nrp2 is less clearly understood. In this chapter, we discuss the identification of Nrp1 and its roles in immune systems.

Neuropilins in Lymphatic Development and Function

Abstract: The lymphatic vascular system is important to maintain extracellular fluid homeostasis and crosstalk with the immune system. Neuropilin 1 and 2 (Nrp1, Nrp2) receptors have emerged as important regulators of lymphangiogenesis. This review summarizes recent findings regarding the roles of Nrp1 and 2 in lymphatic development.

Characterizing Semaphorin-Mediated Effects on Sensory and Motor Axon Pathfinding and Connectivity During Embryonic Development.

Abstract: How are precise connectivity to peripheral targets and corresponding sensory-motor networks established during developmental innervation of the vertebrate extremities? The formation of functional sensory-motor circuits requires highly appropriate temporal and spatial regulation of axon growth which is achieved through the combination of different molecular mechanisms such as communication between heterotypic fiber systems, axon-environment, or axon-glia interactions that ensure proper fasciculation and accurate pathfinding to distal targets Family members of the class 3 semaphorins and their cognate receptors, the neuropilins, were shown to govern various events during wiring of central and peripheral circuits, with mice lacking Sema3-Npn signaling showing deficits in timing of growth, selective fasciculation, guidance fidelity, and coupling of sensory axon growth to motor axons at developmental time points Given the accuracy with which these processes have to interact in a stepwise manner, deficiency of the smallest cog in the wheel may impact severely on the faithful establishment and functionality of peripheral circuitries, ultimately leading to behavioral impairments or even cause the death of the animal Reliable quantitative analyses of sensory-motor fasciculation, extension, and guidance of axons to their cognate target muscles and the skin during development, but also assessment of physiological and behavioral consequences at adult age, are therefore a necessity to extend our understanding of the molecular mechanisms of peripheral circuit formation In this chapter we provide a detailed methodology to characterize class 3 semaphorin-mediated effects on peripheral sensory and motor axon pathfinding and connectivity during embryonic development

Neuropilin-Dependent Signaling and Neuropilin-Independent Signaling of the Guidance Molecule Sema3E

Abstract: Neuropilins are receptors for all but one secreted (class 3) Semaphorins. The exception is Sema3E that directly binds and activates the Plexin-D1 receptor to induce cell repulsion. In this chapter, we review works that identified an unexpected role of Neuropilin-1 as a gating switch in Sema3E/Plexin-D1 signaling, that converts repulsion into attraction, and discuss the implications of this finding for brain wiring.