Mouse Jagged1 Physically Interacts with Notch2 and Other Notch Receptors

Shimizu, Kiyoshí; Chiba, Shigeru; Kumano, Keiki; Hosoya, Noriko; Takahashi, Tsuguhiro; Kanda, Yoshinobu; Hamada, Y.; Yazaki, Yoshio; Hirai, Hisamaru

doi:10.1074/jbc.274.46.32961

Cited by 226 publications

(207 citation statements)

References 53 publications

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“…Jagged1 is a ligand of Notch pathway and has been reported to interact with both Notch1 and Notch2 (Oda et al 20 and Shimizu et al 21 ). To examine whether a blockade of Notch pathway has a protective effect on proteinuria in mice with ADR nephropathy, we administered an antagonistic mAb against Jagged1 intraperitoneally on days 0 and 3 after ADR injection.…”

Section: Resultsmentioning

confidence: 99%

Notch2 activation ameliorates nephrosis

et al. 2014

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Section: Resultsmentioning

confidence: 99%

Notch2 activation ameliorates nephrosis

et al. 2014

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“…Initially, an Fctagged eukaryotically expressed Notch protein containing EGF domains 1-14 (hN1 [1][2][3][4][5][6][7][8][9][10][11][12][13][14] Fc) was immobilized, and a titration was performed by using monomeric human Jagged1 protein spanning the N terminus to EGF3 domains (Jagged1 NE3 ) as analyte. This construct contains the Notch-binding DSL domain in a native context.…”

Section: Resultsmentioning

confidence: 99%

Fringe-mediated extension of O -linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands

Taylor

Takeuchi

Sheppard

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

123

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The Notch signaling pathway is essential for many aspects of development, cell fate determination, and tissue homeostasis. Notch signaling can be modulated by posttranslational modifications to the Notch receptor, which are known to alter both ligand binding and receptor activation. We have modified the ligand-binding region (EGF domains 11-13) of human Notch1 (hN1) with O-fucose and O-glucose glycans and shown by flow cytometry and surface plasmon resonance that the Fringe-catalyzed addition of GlcNAc to the O-fucose at T466 in EGF12 substantially increases binding to Jagged1 and Delta-like 1 (DLL1) ligands. We have subsequently determined the crystal structures of EGF domains 11-13 of hN1 modified with either the O-fucose monosaccharide or the GlcNAc-fucose disaccharide at T466 of EGF12 and observed no change in backbone structure for each variant. Collectively, these data demonstrate a role for GlcNAc in modulating the ligand-binding site in hN1 EGF12, resulting in an increased affinity of this region for ligands Jagged1 and DLL1. We propose that this finding explains the Fringe-catalyzed enhancement of Notch-Delta signaling observed in flies and humans, but suggest that the inhibitory effect of Fringe on Jagged/Serrate mediated signaling involves other regions of Notch.glycosylation | mass spectrometry | X-ray

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“…Although it is not known which DSL proteins can activate which Notch molecules, the DSL proteins Jagged1, Jagged2, and Delta1 have been reported to bind Notch2 and subsequently induce processing, indicating that multiple DSL proteins can activate a specific Notch molecule (22). Furthermore, soluble forms of the extracellular domain of Jagged1 can physically interact with Notch1, Notch2, and Notch3 in binding assays (23,24). Taken together, these data indicate that Jagged1 can bind all Notch receptors leading to activation of signaling in a similar manner.…”

mentioning

confidence: 99%

The C-terminal PDZ-Ligand of JAGGED1 Is Essential for Cellular Transformation

Ascano

Beverly

Capobianco

2003

Journal of Biological Chemistry

111

113

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JAGGED1 is a member of the Delta/Serrate/Lag-2 (DSL) family of proteins that are cell-bound ligands for Notch receptors. Initiation of Notch signaling occurs through a series of proteolytic events upon the binding of Notch to a DSL protein presented on neighboring cells. Whether DSL proteins themselves are capable of initiating an intrinsic signaling mechanism within the cell they are expressed is not known. Aberrant misexpression of JAGGED1 and DELTA1 has been documented in several human tumors; however, the mechanism by which misexpression of JAGGED1 contributes to oncogenesis has not been elucidated. We report that expression of human JAGGED1 transforms RKE cells in culture, therefore providing a model system to elucidate the function of DSL proteins. JAGGED1-mediated transformation occurs in a dose-dependent manner and requires a PDZ-ligand at the C terminus. Mutation of the PDZ-ligand did not affect the ability of JAGGED1 to initiate Notch signaling in neighboring cells. However, the PDZ-ligand is required for changes in the expression of JAGGED1 target genes and transcriptional activation of luciferase reporter constructs. Our data indicate the existence of a novel PDZ-dependent signaling pathway intrinsic to JAGGED1. We propose a bi-directional signaling model such that DSL proteins may have two distinct functions: to initiate Notch signaling in a neighboring cell and to initiate a PDZ-dependent signaling mechanism in the DSL-expressing cell. Moreover, we conclude that this intrinsic signaling mechanism of JAGGED1 may partly provide a link between aberrant misexpression of JAGGED1 and tumorigenesis.

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Mouse Jagged1 Physically Interacts with Notch2 and Other Notch Receptors

Cited by 226 publications

References 53 publications

Notch2 activation ameliorates nephrosis

Notch2 activation ameliorates nephrosis

Fringe-mediated extension of O -linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands

The C-terminal PDZ-Ligand of JAGGED1 Is Essential for Cellular Transformation

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