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Snorri S Thorgeirsson - One of the best experts on this subject based on the ideXlab platform.

  • Neuropilin 1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment
    Cancer Research, 2012
    Co-Authors: Usman Yaqoob, Uday Shergill, Kumaravelu Jagavelu, Zhimin Geng, Thiago M De Assuncao, Anna Szabolcs, Snorri S Thorgeirsson, Martin A Schwartz, Ju Dong Yang, Richard Lorne Ehman
    Abstract:

    The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here, we report that Neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin that promote α5β1 integrin–dependent fibronectin fibril assembly, matrix stiffness, and tumor growth. Tumor growth and fibronectin fibril assembly were reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo . Mechanistically, the increase in fibronectin fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl that augmented α5β1 fibronectin fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of fibronectin fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment. Cancer Res; 72(16); 4047–59. ©2012 AACR .

  • Neuropilin 1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment
    Cancer Research, 2012
    Co-Authors: Usman Yaqoob, Uday Shergill, Kumaravelu Jagavelu, Zhimin Geng, Thiago M De Assuncao, Anna Szabolcs, Sheng Cao, Meng Yin, Ying Cao, Snorri S Thorgeirsson
    Abstract:

    The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here, we report that Neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin that promote α5β1 integrin-dependent fibronectin fibril assembly, matrix stiffness, and tumor growth. Tumor growth and fibronectin fibril assembly were reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo. Mechanistically, the increase in fibronectin fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl that augmented α5β1 fibronectin fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of fibronectin fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment.

Usman Yaqoob - One of the best experts on this subject based on the ideXlab platform.

  • Neuropilin 1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment
    Cancer Research, 2012
    Co-Authors: Usman Yaqoob, Uday Shergill, Kumaravelu Jagavelu, Zhimin Geng, Thiago M De Assuncao, Anna Szabolcs, Snorri S Thorgeirsson, Martin A Schwartz, Ju Dong Yang, Richard Lorne Ehman
    Abstract:

    The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here, we report that Neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin that promote α5β1 integrin–dependent fibronectin fibril assembly, matrix stiffness, and tumor growth. Tumor growth and fibronectin fibril assembly were reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo . Mechanistically, the increase in fibronectin fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl that augmented α5β1 fibronectin fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of fibronectin fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment. Cancer Res; 72(16); 4047–59. ©2012 AACR .

  • Neuropilin 1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment
    Cancer Research, 2012
    Co-Authors: Usman Yaqoob, Uday Shergill, Kumaravelu Jagavelu, Zhimin Geng, Thiago M De Assuncao, Anna Szabolcs, Sheng Cao, Meng Yin, Ying Cao, Snorri S Thorgeirsson
    Abstract:

    The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here, we report that Neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin that promote α5β1 integrin-dependent fibronectin fibril assembly, matrix stiffness, and tumor growth. Tumor growth and fibronectin fibril assembly were reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo. Mechanistically, the increase in fibronectin fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl that augmented α5β1 fibronectin fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of fibronectin fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment.

Stephen M. Strittmatter - One of the best experts on this subject based on the ideXlab platform.

  • plexin Neuropilin 1 complexes form functional semaphorin 3a receptors
    Cell, 1999
    Co-Authors: Takuya Takahashi, Fumio Nakamura, Robert G. Kalb, Alyson E Fournier, Li Hsien Wang, Yasunori Murakami, Hajime Fujisawa, Stephen M. Strittmatter
    Abstract:

    Class 1 and 3 semaphorins repulse axons but bind to different cell surface proteins. We find that the two known semaphorin-binding proteins, plexin 1 (Plex 1) and Neuropilin-1 (NP-1), form a stable complex. Plex 1 alone does not bind semaphorin-3A (Sema3A), but the NP-1/Plex 1 complex has a higher affinity for Sema3A than does NP-1 alone. While Sema3A binding to NP-1 does not alter nonneuronal cell morphology, Sema3A interaction with NP-1/Plex 1 complexes induces adherent cells to round up. Expression of a dominant-negative Plex 1 in sensory neurons blocks Sema3A-induced growth cone collapse. Sema3A treatment leads to the redistribution of growth cone NP-1 and plexin into clusters. Thus, physiologic Sema3A receptors consist of NP-1/plexin complexes.

  • growth cone Neuropilin 1 mediates collapsin 1 sema iii facilitation of antero and retrograde axoplasmic transport
    Journal of Neurobiology, 1999
    Co-Authors: Yoshio Goshima, Takuya Takahashi, Stephen M. Strittmatter, Fumio Nakamura, Toshifumi Takenaka, Hideaki Hori, Yukio Sasaki, Tao Yang, Masako Kagoshimamaezono, Yoshimi Misu
    Abstract:

    Collapsin-1/Sema III, a member of the semaphorin family, has been implicated in axonal pathfinding as a repulsive guidance cue. Cellular and molecular mechanisms by which collapsin-1 exerts its action are not fully understood. Collapsin-1 induces growth cone collapse via a pathway which may include Neuropilin-1, a cellsurface collapsin-1 binding protein, as well as intracellular CRMP-62 and heterotrimeric G proteins. We previously identified a second action of collapsin-1, the facilitation of antero- and retrograde axoplasmic transport. This response occurs via a mechanism distinct from that causing growth cone collapse. To investigate the possible involvement of Neuropilin-1 in the action of collapsin-1 on axoplasmic transport, we produced a soluble Neuropilin-1 (sNP-1) lacking the transmembrane and intracellular region. sNP-1 progressively displaced the dose-response curve for collapsin-1 to induce growth cone collapse to higher concentrations. sNP-1 also inhibited collapsin-1-induced augmentation of both antero- and retrograde axoplasmic transport. Furthermore, an anti-Neuropilin-1 antibody blocked the collapsin-induced axoplasmic transport. These results together indicate that Neuropilin-1 mediates collapsin-1 action on axoplasmic transport. To visualize collapsin-1 binding to endogenous Neuropilin-1, we used a truncated collapsin-1-alkaline phosphatase fusion protein (CAP-4). CAP-4 stains the growth cone, neurite, and cell body. However, local application of collapsin-1 to growth cone but to neither neurite nor cell body promotes axoplasmic transport. Thus, growth cone NP-1 mediates the facilitatory action of collapsin-1 on antero- and retrograde axoplasmic transport.

  • Neuropilin-1 Extracellular Domains Mediate Semaphorin D/III-Induced Growth Cone Collapse
    Neuron, 1998
    Co-Authors: Fumio Nakamura, Takuya Takahashi, Masaki Tanaka, Robert G. Kalb, Stephen M. Strittmatter
    Abstract:

    Abstract Somatosensory axon outgrowth is repulsed when soluble semaphorin D (semD) binds to growth cone Neuropilin-1 (Npn-1). Here, semD ligand binding studies of Npn-1 mutants demonstrate that the sema domain binds to the amino-terminal quarter, or complement-binding (CUB) domain, of Npn-1. By herpes simplex virus– (HSV-) mediated expression of Npn-1 mutants in chick retinal ganglion cells, we show that semD-induced growth cone collapse requires two segments of the ectodomain of Npn-1, the CUB domain and the juxtamembrane portion, or MAM (meprin, A5, μ) domain. In contrast, the transmembrane segment and cytoplasmic tail of Npn-1 are not required for biologic activity. These data imply that the CUB and MAM ectodomains of Npn-1 interact with another transmembrane growth cone protein that in turn transduces a semD signal into axon repulsion.

  • Semaphorins A and E act as antagonists of Neuropilin-1 and agonists of Neuropilin-2 receptors.
    Nature neuroscience, 1998
    Co-Authors: Takuya Takahashi, Fumio Nakamura, Robert G. Kalb, Zhao Jin, Stephen M. Strittmatter
    Abstract:

    Neuropilin-1 (NP-1) has been identified as a necessary component of a semaphorin D (SemD) receptor that repulses dorsal root ganglion (DRG) axons during development. SemA and SemE are related to SemD and bind to NP-1, but do not repulse DRG axons. By expressing NP-1 in retinal neurons and NP-2 in DRG neurons, we demonstrate that Neuropilins are sufficient to determine the functional specificity of semaphorin responsiveness. SemA and SemE block SemD binding to NP-1 and abolish SemD repulsion in axons expressing NP-1. SemA and SemE seem to have a newly discovered protein antagonist capacity at NP-1 receptors, whereas they act as agonists at receptors containing NP-2.

Dipak Panigrahy - One of the best experts on this subject based on the ideXlab platform.

  • Neuropilin 1 receptor is up regulated in dysplastic epithelium and oral squamous cell carcinoma
    American Journal of Pathology, 2016
    Co-Authors: Shokoufeh Shahrabifarahani, Marina Gallottini, Fabiana Martins, Erik Li, Dayna R Mudge, Hironao Nakayama, Kyoko Hida, Dipak Panigrahy
    Abstract:

    Neuropilins are receptors for disparate ligands, including proangiogenic factors such as vascular endothelial growth factor and inhibitory class 3 semaphorin (SEMA3) family members. Differentiated cells in skin epithelium and cutaneous squamous cell carcinoma highly express the Neuropilin-1 (NRP1) receptor. We examined the expression of NRP1 in human and mouse oral mucosa. NRP1 was significantly up-regulated in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC). NRP1 receptor localized to the outer suprabasal epithelial layers in normal tongue, an expression pattern similar to the normal skin epidermis. However, dysplastic tongue epithelium and OSCC up-regulated NRP1 in basal and proliferating epithelial layers, a profile unseen in cutaneous squamous cell carcinoma. NRP1 up-regulation is observed in a mouse carcinogen-induced OSCC model and in human tongue OSCC biopsies. Human OSCC cell lines express NRP1 protein in vitro and in mouse tongue xenografts. Sites of capillary infiltration into orthotopic OSCC tumors correlate with high NRP1 expression. HSC3 xenografts, which express the highest NRP1 levels of the cell lines examined, showed massive intratumoral lymphangiogenesis. SEMA3A inhibited OSCC cell migration, suggesting that the NRP1 receptor was bioactive in OSCC. In conclusion, NRP1 is regulated in the oral epithelium and is selectively up-regulated during epithelial dysplasia. NRP1 may function as a reservoir to sequester proangiogenic ligands within the neoplastic compartment, thereby recruiting neovessels toward tumor cells.

Richard Lorne Ehman - One of the best experts on this subject based on the ideXlab platform.

  • Neuropilin 1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment
    Cancer Research, 2012
    Co-Authors: Usman Yaqoob, Uday Shergill, Kumaravelu Jagavelu, Zhimin Geng, Thiago M De Assuncao, Anna Szabolcs, Snorri S Thorgeirsson, Martin A Schwartz, Ju Dong Yang, Richard Lorne Ehman
    Abstract:

    The tumor microenvironment, including stromal myofibroblasts and associated matrix proteins, regulates cancer cell invasion and proliferation. Here, we report that Neuropilin-1 (NRP-1) orchestrates communications between myofibroblasts and soluble fibronectin that promote α5β1 integrin–dependent fibronectin fibril assembly, matrix stiffness, and tumor growth. Tumor growth and fibronectin fibril assembly were reduced by genetic depletion or antibody neutralization of NRP-1 from stromal myofibroblasts in vivo . Mechanistically, the increase in fibronectin fibril assembly required glycosylation of serine 612 of the extracellular domain of NRP-1, an intact intracellular NRP-1 SEA domain, and intracellular associations between NRP-1, the scaffold protein GIPC, and the nonreceptor tyrosine kinase c-Abl that augmented α5β1 fibronectin fibril assembly activity. Analysis of human cancer specimens established an association between tumoral NRP-1 levels and clinical outcome. Our findings indicate that NRP-1 activates the tumor microenvironment, thereby promoting tumor growth. These results not only identify new molecular mechanisms of fibronectin fibril assembly but also have important implications for therapeutic targeting of the myofibroblast in the tumor microenvironment. Cancer Res; 72(16); 4047–59. ©2012 AACR .