A Notch Ligand, Delta-Like 1 Functions As an Adhesion Molecule for Mast Cells

Murata, Akihiko; Okuyama, Kazuki; Sakano, Seiji; Kajiki, Masahiro; Hirata, Tomohisa; Yagita, Hideo; Zúñiga‐Pflücker, Juan Carlos; Miyake, Kensuke; Akashi-Takamura, Sachiko; Moriwaki, Shinichi; Niida, Shumpei; Yoshino, Miya; Hayashi, S.

doi:10.4049/jimmunol.1000195

Cited by 32 publications

(35 citation statements)

References 68 publications

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“…6). It has been previously reported that NOTCH-ligand interactions affected cell-cell contacts and adhesion in cardiovascular abnormalities (28) and chronic inflammation (29). Similarly, NOTCH signaling activation was dispensable in their findings.…”

Section: Discussionmentioning

confidence: 71%

The NOTCH Ligand JAGGED2 Promotes Pancreatic Cancer Metastasis Independent of NOTCH Signaling Activation

et al. 2015

Molecular Cancer Therapeutics

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease with a high rate of metastasis. Numerous signaling events have been implicated in the molecular pathogenesis of this neoplasm. Aberrantly high expression of JAGGED2, one of the NOTCH ligands, often occurs in human PDAC. However, what role JAGGED2 plays in the disease development and whether JAGGED2 executes its function through activating NOTCH signaling remain to be determined. We report here that JAGGED2 plays a critical role in promoting PDAC metastasis in vitro and in vivo. Depletion of JAGGED2, but not its homolog JAGGED1, profoundly inhibited both migration and invasion without influencing cell proliferation. Furthermore, reconstitution of JAGGED2 expression rescued the migratory defect. Surprisingly, neither pharmacologic nor genetic inhibition of NOTCH downstream signaling resulted in obvious defect in metastasis. Instead, depletion of NOTCH1 expression per se gave rise to migratory defects similar to JAGGED2 ablation. Moreover, blockade of ligand-receptor interaction by a specific JAGGED2-Fc fusion protein dramatically inhibited PDAC cell migration, suggesting that tumor metastasis relies on physical interactions of JAGGED2-NOTCH1 but not Notch downstream signaling activation. Taken together, our data reveal a novel role of NOTCH in regulation of PDAC metastasis, and identify JAGGED2 as a critical mediator in this event. These findings also provide rationale for developing small molecules or biologic agents targeting JAGGED2 for therapeutic intervention.

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Section: Discussionmentioning

confidence: 71%

The NOTCH Ligand JAGGED2 Promotes Pancreatic Cancer Metastasis Independent of NOTCH Signaling Activation

et al. 2015

Molecular Cancer Therapeutics

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“…Additionally, RBP-J-deficient DCs showed diminished expression of CXCR4 and CCR7, critical chemokine receptors for DC differentiation and migration (39,49). Also, Notch molecules have been involved in other important functions such as the communication between DCs and NK cells (50), protection from apoptosis (51), and adhesion between mast cells and stromal cells (52).…”

Section: Discussionmentioning

confidence: 99%

Ligation of Notch Receptors in Human Conventional and Plasmacytoid Dendritic Cells Differentially Regulates Cytokine and Chemokine Secretion and Modulates Th Cell Polarization

Pérez-Cabezas

Naranjo-Gómez

Bastos-Amador

et al. 2011

The Journal of Immunology

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Notch signaling is involved in multiple cellular processes. Recent data also support the prominent role of Notch signaling in the regulation of the immune response. In this study, we analyzed the expression and function of Notch receptors and ligands on both human blood conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs). The expression and modulation upon TLR activation of Notch molecules partially differed between cDCs and pDCs, but functional involvement of the Notch pathway in both cell types was clearly revealed by specific inhibition using DAPT. Beyond the induction of Notch target genes and modulation of maturation markers, Notch pathway was also involved in a differential secretion of some specific cytokines/chemokines by DC subsets. Whereas Notch ligation induced IL-10 and CCL19 secretion in cDCs, Notch inhibition resulted in a diminished production of these proteins. With regard to pDCs, Notch activation induced TNF-α whereas Notch inhibition significantly abrogated the secretion of CCL19, CXCL9, CXCL10, and TNF-α. Additionally, Notch modulation of DC subsets differentially affected Th polarization of allostimulated T cells. Our results suggest that the Notch pathway may function as an additional mechanism controlling human DC responses, with differential activity on cDCs and pDCs. This control mechanism may ultimately contribute to define the local milieu promoted by these cells under the particular conditions of the immune response.

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“…Thus, because DLL1 participates in fat metabolism, 26,27 it could be used as an indicator of M. tuberculosis infection. To explore DLL1 as a potential new tool for the diagnosis of TBM, the present study adopted an enzyme-linked immunosorbent assay (ELISA) for the quantitative measurement of DLL1 in CSF and serum samples from different patient groups: those with infection of the CNS, those with intracranial metastatic tumour and those with no diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Detection of Delta-like 1 ligand for the diagnosis of tuberculous meningitis: An effective and rapid diagnostic method

Peng

Zhou

et al. 2014

J Int Med Res

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Objective: To investigate the diagnostic value of Delta-like 1 ligand (DLL1) in cerebrospinal fluid (CSF) and serum, in tuberculous meningitis (TBM). Methods: Patients with a definite diagnosis of central nervous system infection (TBM, viral meningitis/encephalitis or bacterial meningitis) were prospectively enrolled alongside patients with intracranial metastatic tumour and patients with no diagnosis (who served as controls). DLL1 content in CSF and serum was measured quantitatively by enzyme-linked immunosorbent assay; analyses were blinded. Results: A total of 173 patients were enrolled: 62 with TBM; 38 with viral meningitis/encephalitis; 26 with bacterial meningitis; 17 with intracranial metastatic tumour; 30 with no diagnosis. CSF DLL1 content was highest for TBM; there were no differences in CSF DLL1 between the other groups. Serum DLL1 content was highest for the TBM and intracranial metastatic tumour groups, with significant differences between the TBM group and the viral meningitis/encephalitis, bacterial meningitis and nondiagnosed groups. There were no differences in serum DLL1 between the viral meningitis/encephalitis, bacterial meningitis and nondiagnosed groups, or between the TBM group and the tumour group. Conclusion: As a new biomarker, DLL1 may be of great clinical importance in the diagnosis of TBM.

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A Notch Ligand, Delta-Like 1 Functions As an Adhesion Molecule for Mast Cells

Cited by 32 publications

References 68 publications

The NOTCH Ligand JAGGED2 Promotes Pancreatic Cancer Metastasis Independent of NOTCH Signaling Activation

The NOTCH Ligand JAGGED2 Promotes Pancreatic Cancer Metastasis Independent of NOTCH Signaling Activation

Ligation of Notch Receptors in Human Conventional and Plasmacytoid Dendritic Cells Differentially Regulates Cytokine and Chemokine Secretion and Modulates Th Cell Polarization

Detection of Delta-like 1 ligand for the diagnosis of tuberculous meningitis: An effective and rapid diagnostic method

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