Neuropilins in physiological and pathological angiogenesis

Staton, Carolyn A.; Kumar, I; Reed, Malcolm; Brown, Nicola J.

doi:10.1002/path.2182

Cited by 200 publications

(192 citation statements)

References 131 publications

(154 reference statements)

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“…[2][3][4]24,25 More recently, it has been reported that NRP1 might have a role as a novel mediator of the primary immune response, as well as in tissue regeneration and repair. 26 Together these findings suggest that NRPs are multifunctional co-receptors essential for neuronal and cardiovascular development, but potentially have additional functions in diverse physiological and disease-related settings. Thus, and on the basis of the preliminary real-time PCR analyses of microdissected proximal tubular cells from patients with a progressive loss of kidney function, it was of interest to us to study the expression of the two NRP isoforms in renal tissue sections of patients suffering from FSGS.…”

Section: Discussionmentioning

confidence: 95%

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Neuropilin-1 and neuropilin-2 are differentially expressed in human proteinuric nephropathies and cytokine-stimulated proximal tubular cells

Schramek

Sarközi

Lauterberg

et al. 2009

Laboratory Investigation

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Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) are transmembrane glycoproteins with large extracellular domains that interact with class 3 semaphorins, vascular endothelial growth factor (VEGF) family members, and ligands, such as hepatocyte growth factor, platelet-derived growth factor BB, transforming growth factor-b1 (TGF-b1), and fibroblast growth factor2 (FGF2). Neuropilins (NRPs) have been implicated in tumor growth and vascularization, as novel mediators of the primary immune response and in regeneration and repair; however, their role in renal pathophysiology is largely unknown. Here, we report upregulation of tubular and interstitial NRP2 protein expression in patients with focal segmental glomerulosclerosis (FSGS). In an additional cohort of patients with minimal change disease (MCD), membranous nephropathy (MN), and FSGS, elevated NRP2 mRNA expression in kidney biopsies inversely correlated with estimated glomerular filtration rate (eGFR) at the time of biopsy. Furthermore, upregulation of NRP2 mRNA correlated with post-bioptic decline of kidney function. Expression of NRP1 and NRP2 in human proximal tubular cells (PTCs) was differentially affected after stimulation with TGF-b1, interleukin-1b (IL-1b), and oncostatin M (OSM). Although the pro-fibrotic mediators, TGF-b1 and IL-1b, induced upregulation of NRP2 expression but downregulation of NRP1 expression, OSM stimulated the expression of both NRP1 and NRP2. Basal and OSM-induced NRP1 mRNA expression, as well as TGF-b1-induced NRP2 mRNA and protein expression were partially mediated by MEK1/2-ERK1/2 signaling. This is the first report suggesting a differential role of NRP1 and NRP2 in renal fibrogenesis, and TGF-b1, IL-1b, and OSM represent the first ligands known to stimulate NRP2 expression in mammalian cells.

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Section: Discussionmentioning

confidence: 95%

“…[8][9][10] The cells (passages [20][21][22][23][24][25][26][27][28][29][30] were grown at 371C in a humidified 5% CO 2 atmosphere, and split at a 1:10 ratio, once a week. After growth to a subconfluent state, cells were washed once, made quiescent by incubation in serum-and supplementfree medium for 48 h, and then used for experiments.…”

Section: Cell Culturementioning

confidence: 99%

Neuropilin-1 and neuropilin-2 are differentially expressed in human proteinuric nephropathies and cytokine-stimulated proximal tubular cells

Schramek

Sarközi

Lauterberg

et al. 2009

Laboratory Investigation

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“…The role of Sema3A in glioblastoma dispersal T Bagci et al Hu et al, 2007;Staton et al, 2007;Vales et al, 2007). In addition to its role as a Sema3A receptor, neuropilin-1 is a co-receptor for a specific isoform of VEGF165 and guides endothelial cell migration during vascular morphogenesis (Soker et al, 1998;Lee et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

et al. 2009

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Glioblastoma multiforme (GBM) is the most malignant glioma type with diffuse borders due to extensive tumor cell infiltration. Therefore, understanding the mechanism of GBM cell dispersal is critical for developing effective therapies to limit infiltration. We identified neuropilin-1 as a mediator of cancer cell invasion by a functional proteomic screen and showed its role in GBM cells. Neuropilin-1 is a receptor for semaphorin3A (Sema3A), a secreted chemorepellent that facilitates axon guidance during neural development. Although neuropilin-1 expression in GBMs was previously shown, its role as a Sema3A receptor remained elusive. Using fluorophore-assisted light inactivation and RNA interference , we showed that neuropilin-1 is required for GBM cell migration. We also showed that GBM cells secrete Sema3A endogenously, and RNA interferencemediated downregulation of Sema3A inhibits migration and alters cell morphology that is dependent on Rac1 activity. Sema3A depletion also reduces dispersal, which is recovered by supplying Sema3A exogenously. Extracellular application of Sema3A decreases cell-substrate adhesion in a neuropilin-1-dependent manner. Using immunohistochemistry, we showed that Sema3A is overexpressed in a subset of human GBMs compared with the non-neoplastic brain. Together, these findings implicate Sema3A as an autocrine signal for neuropilin-1 to promote GBM dispersal by modulating substrate adhesion and suggest that targeting Sema3A-neuropilin-1 signaling may limit GBM infiltration.

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“…Although slp-76-ADAP interactions controlled the accumulation of iNKT cells in the spleen, the participating chemokine(s) and/or adhesion factor(s) still need to be identified. In contrast to CD11b and LFA-1, slp-76 ADAP-independently regulated the expression of NP-1, a transmembrane glycoprotein, which binds to VEGF receptors and exhibits various functions, many of them yet to be defined [80][81][82][83]. Here, we identified NP-1 as critical molecule for the accumulation of iNKT cells in peripheral lymph nodes.…”

Section: Discussionmentioning

confidence: 88%

A mutation within the SH2 domain of slp‐76 regulates the tissue distribution and cytokine production of iNKT cells in mice

et al. 2016

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TCR ligation is critical for the selection, activation, and integrin expression of T lymphocytes. Here, we explored the role of the TCR adaptor protein slp-76 on iNKT-cell biology. Compared to B6 controls, slp-76 ace/ace mice carrying a missense mutation (Thr428Ile) within the SH2-domain of slp-76 showed an increase in iNKT cells in the thymus and lymph nodes, but a decrease in iNKT cells in spleens and livers, along with reduced ADAP expression and cytokine response. A comparable reduction in iNKT cells was observed in the livers and spleens of ADAP-deficient mice. Like ADAP −/− iNKT cells, slp-76 ace/ace iNKT cells were characterized by enhanced CD11b expression, correlating with an impaired induction of the TCR immediate-early gene Nur77 and a decreased adhesion to ICAM-1. Furthermore, CD11b-intrinsic effects inhibited cytokine release, concanavalin A-mediated inflammation, and iNKT-cell accumulation in the liver. Unlike B6 and ADAP −/− mice, the expression of the transcription factors Id3 and PLZF was reduced, whereas NP-1-expression was enhanced in slp-76 ace/ace mice. Blockade of NP-1 decreased the recovery of iNKT cells from peripheral lymph nodes, identifying NP-1 as an iNKT-cell-specific adhesion factor. Thus, slp-76 contributes to the regulation of the tissue distribution, PLZF, and cytokine expression of iNKT cells via ADAP-dependent and -independent mechanisms.Keywords: ADAP r Cytokine r iNKT cell r Integrin r slp-76Additional supporting information may be found in the online version of this article at the publisher's web-site Eur. J. Immunol. 2016Immunol. . 46: 2121Immunol. -2136 Introduction iNKT cells express a panoply of NK-cell receptors [1] and a canonical TCR through which they recognize (glyco-)lipid antigens [2]. iNKT cells activate similar signaling cascades after TCR ligation like other T lymphocytes [3], but utilize unique transcription factors for their development such as the promyelocytic leukemia zinc finger (PLZF) [4][5][6]. According to two different developmental models PLZF characterizes distinct maturation stages and polarized subsets. The sequential lineage model suggests a gradual decrease of PLZFexpression following selection of iNKT cells which show a Th2-dominated cytokine profile during earlier and a Th1-dominated cytokine profile during later stages of intrathymic maturation [1,7]. The second model describes lineage diversification and simultaneous differentiation into Th1-, Th2-, or Th17-polarized subsets that are defined by the level of PLZF-expression [8]. Although many iNKT cells release both Th1 and Th2 cytokines on a single cell level [9], the production of IL-17 and IFN-γ is mutually exclusive within NK1.1 − cells [10][11][12]. Several transcription factors, such as Egr2, T-bet, ThPOK, Id2, Id3, and the Tec kinases Itk and Rlk have been implicated in the differentiation of iNKT cell subsets [6,8,[13][14][15][16][17] which home to distinct tissues. Specifically, liver and spleen constitute the main source for the Th1-polarized sublineage which is PLZF low . Th2-or ...

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Neuropilins in physiological and pathological angiogenesis

Cited by 200 publications

References 131 publications

Neuropilin-1 and neuropilin-2 are differentially expressed in human proteinuric nephropathies and cytokine-stimulated proximal tubular cells

Neuropilin-1 and neuropilin-2 are differentially expressed in human proteinuric nephropathies and cytokine-stimulated proximal tubular cells

Autocrine semaphorin 3A signaling promotes glioblastoma dispersal

A mutation within the SH2 domain of slp‐76 regulates the tissue distribution and cytokine production of iNKT cells in mice

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