Interactions of Multiple Heparin Binding Growth Factors with Neuropilin-1 and Potentiation of the Activity of Fibroblast Growth Factor-2

West, David C.; Rees, C.; Duchesne, Laurence; Patey, Susannah J.; Terry, Carla J.; Turnbull, Jeremy E.; Delehedde, Maryse; Heegaard, Christian W.; Allain, Fabrice; Vanpouille, Christophe; Ron, Dina; Fernig, David G.

doi:10.1074/jbc.m410924200

Cited by 151 publications

(155 citation statements)

References 56 publications

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“…A plausible mechanism of NRP1 stimulation of tumor progression in our study and the pancreatic cancer model is that NRP1 enhances endogenous signaling modulating tumor cell function independent of VEGF. Our results of NRP1 potentiation of the HGF/SF/c-Met signaling pathway in glioma cells agree with another recent study showing that that NRP1 not only interacts directly with multiple heparin-binding growth factors, such as FGF-2, FGF-4 and HGF/SF, but also potentiates stimulation of FGF-2 on endothelial cells (West et al, 2005). In addition, the increased sensitivity to HGF/SF/c-Met signaling by endogenously expressed NRP1 in glioma cells is analogous to the increase in sensitivity to FGF-2 caused by the addition of a soluble NRP1 dimer to endothelial cells in the aforementioned study.…”

Section: Discussionsupporting

confidence: 82%

“…A recent study demonstrated NRP1 also interacts with several heparin-binding growth factors, such as FGF-2, FGF-4 and HGF/SF, and potentiates the growth stimulatory activity of FGF-2 on endothelial cells (West et al, 2005). As HGF/SF and FGF-2 were shown to stimulate cell growth through receptor-mediated autocrine signaling in glioma cells (Abounader and Laterra, 2005), we performed enzyme-linked immunosorbent assay (ELISA) and determined whether the autocrine signaling activities of these growth factors were involved in the NRP1-stimulated U87MG cell survival and growth.…”

Section: Nrp1 Promotes U87mg Cell Growth Through Enhancing Autocrine mentioning

confidence: 99%

“…Additionally, the activation of signaling molecules such as extracellular signal-regulated kinase (ERK) and Bcl-2 antagonist of cell death (Bad) is involved in the HGF/SF/c-Met pathway in cancer cells (Abounader and Laterra, 2005). NRP1 was recently demonstrated to interact directly with a subset of heparinbinding growth factors, such as fibroblast growth factor-2 (FGF-2), FGF-4 and HGF/SF and potentiates FGF-2 stimulation of endothelial cells (West et al, 2005), suggesting that NRP1 expression in glioma cells may augment HGF/SF/c-Met stimulation of tumor progression through an autocrine loop.…”

Section: Introductionmentioning

confidence: 99%

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Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway

et al. 2007

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Neuropilin-1 (NRP1) functions as a coreceptor through interaction with plexin A1 or vascular endothelial growth factor (VEGF) receptor during neuronal development and angiogenesis. NRP1 potentiates the signaling pathways stimulated by semaphorin 3A and VEGF-A in neuronal and endothelial cells, respectively. In this study, we investigate the role of tumor cell-expressed NRP1 in glioma progression. Analyses of human glioma specimens (WHO grade I-IV tumors) revealed a significant correlation of NRP1 expression with glioma progression. In tumor xenografts, overexpression of NRP1 by U87MG gliomas strongly promoted tumor growth and angiogenesis. Overexpression of NRP1 by U87MG cells stimulated cell survival through the enhancement of autocrine hepatocyte growth factor/scatter factor (HGF/SF)/c-Met signaling. NRP1 not only potentiated the activity of endogenous HGF/SF on glioma cell survival but also enhanced HGF/SFpromoted cell proliferation. Inhibition of HGF/SF, c-Met and NRP1 abrogated NRP1-potentiated autocrine HGF/SF stimulation. Furthermore, increased phosphorylation of c-Met correlated with glioma progression in human glioma biopsies in which NRP1 is upregulated and in U87MG NRP1-overexpressing tumors. Together, these data suggest that tumor cell-expressed NRP1 promotes glioma progression through potentiating the activity of the HGF/SF autocrine c-Met signaling pathway, in addition to enhancing angiogenesis, suggesting a novel mechanism of NRP1 in promoting human glioma progression.

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Section: Discussionsupporting

confidence: 82%

Section: Nrp1 Promotes U87mg Cell Growth Through Enhancing Autocrine mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway

et al. 2007

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“…FGF signaling plays an important role in branching morphogenesis (Affolter et al, 2009), including morphogenesis of the mammary gland (Lu et al, 2006). Interestingly, however, FGF-induced branching of mammary epithelial cells does not appear to involve NRP2, although there is evidence that the NRPs can interact with and modulate the function of specific heparin-binding factor receptors, including FGF receptors (West et al, 2005).…”

Section: Research Articlementioning

confidence: 99%

Neuropilin-2 promotes branching morphogenesis in the mouse mammary gland

et al. 2011

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SUMMARYAlthough the neuropilins were characterized as semaphorin receptors that regulate axon guidance, they also function as vascular endothelial growth factor (VEGF) receptors and contribute to the development of other tissues. Here, we assessed the role of NRP2 in mouse mammary gland development based on our observation that NRP2 is expressed preferentially in the terminal end buds of developing glands. A floxed NRP2 mouse was bred with an MMTV-Cre strain to generate a mammary gland-specific knockout of NRP2. MMTV-Cre;NRP2 loxP/loxP mice exhibited significant defects in branching morphogenesis and ductal outgrowth compared with either littermate MMTV-Cre;NRP2 +/loxP or MMTV-Cre mice. Mechanistic insight into this morphological defect was obtained from a mouse mammary cell line in which we observed that VEGF 165 , an NRP2 ligand, induces branching morphogenesis in 3D cultures and that branching is dependent upon NRP2 as shown using shRNAs and a function-blocking antibody. Epithelial cells in the mouse mammary gland express VEGF, supporting the hypothesis that this NRP2 ligand contributes to mammary gland morphogenesis. Importantly, we demonstrate that VEGF and NRP2 activate focal adhesion kinase (FAK) and promote FAKdependent branching morphogenesis in vitro. The significance of this mechanism is substantiated by our finding that FAK activation is diminished significantly in developing MMTV-Cre;NRP2 loxP/loxP mammary glands compared with control glands.Together, our data reveal a VEGF/NRP2/FAK signaling axis that is important for branching morphogenesis and mammary gland development. In a broader context, our data support an emerging hypothesis that directional outgrowth and branching morphogenesis in a variety of tissues are influenced by signals that were identified initially for their role in axon guidance.

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“…In contrast, overexpression of NRP-1 leads to over-stimulation of blood vessel formation (Kitsukawa et al, 1995). Studies have shown that NRP-1interacts with a subset of heparin binding proteins like FGF-1, FGF-2, FGF-4, FGF-7, FGF receptor-1, and HGF/SF (West et al, 2005). Investigation of the role of NRP-1 in human glioma progression, Hu et al (Hu et al, 2007) have shown that NRP-1 expression correlates with tumor progression in clinical setting, and that NRP-1 expression promotes tumor growth and survival through an autocrine HGF/SF/c-met signaling pathway.…”

Section: On the Role Of Cell Surface Chondroitin Sulfates And Their Cmentioning

confidence: 99%

On the Role of Cell Surface Chondroitin Sulfates and Their Core Proteins in Breast Cancer Metastasis

Kieber-Emmons¹,

Jousheghany²,

Monzavi‐Karbassi³

2011

Breast Cancer - Focusing Tumor Microenvironment, Stem Cells and Metastasis

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Interactions of Multiple Heparin Binding Growth Factors with Neuropilin-1 and Potentiation of the Activity of Fibroblast Growth Factor-2

Cited by 151 publications

References 56 publications

Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway

Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway

Neuropilin-2 promotes branching morphogenesis in the mouse mammary gland

On the Role of Cell Surface Chondroitin Sulfates and Their Core Proteins in Breast Cancer Metastasis

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