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  1. Article ; Online: N-glycan on N262 of FGFR3 regulates the intracellular localization and phosphorylation of the receptor.

    Hashimoto, Ukichiro / Fujitani, Naoki / Uehara, Yasuaki / Okamoto, Hiromi / Saitou, Atsushi / Ito, Fumie / Ariki, Shigeru / Shiratsuchi, Akiko / Hasegawa, Yoshihiro / Takahashi, Motoko

    Biochimica et biophysica acta. General subjects

    2024  Volume 1868, Issue 4, Page(s) 130565

    Abstract: N-glycosylation and proper processing of N-glycans are required for the function of membrane proteins including cell surface receptors. Fibroblast growth factor receptor (FGFR) is involved in a wide variety of biological processes including embryonic ... ...

    Abstract N-glycosylation and proper processing of N-glycans are required for the function of membrane proteins including cell surface receptors. Fibroblast growth factor receptor (FGFR) is involved in a wide variety of biological processes including embryonic development, osteogenesis, angiogenesis, and cell proliferation. Human FGFR3 contains six potential N-glycosylation sites, however, the roles of glycosylation have not been elucidated. The site-specific profiles of N-glycans of the FGFR3 extracellular domain expressed and secreted by CHO-K1 cells were examined, and glycan occupancies and structures of four sites were determined. The results indicated that most sites were fully occupied by glycans, and the dominant populations were the complex type. By examining single N-glycan deletion mutants of FGFR3, it was found that N262Q mutation significantly increased the population with oligomannose-type N-glycans, which was localized in the endoplasmic reticulum. Protein stability assay suggested that fraction with oligomannose-type N-glycans in the N262Q mutant is more stable than those in the wild type and other mutants. Furthermore, it was found that ligand-independent phosphorylation was significantly upregulated in N262Q mutants with complex type N-glycans. The findings suggest that N-glycans on N262 of FGFR3 affect the intracellular localization and phosphorylation status of the receptor.
    MeSH term(s) Cricetinae ; Animals ; Humans ; Phosphorylation ; Glycosylation ; CHO Cells ; Cricetulus ; Polysaccharides/metabolism ; Biological Phenomena ; Receptor, Fibroblast Growth Factor, Type 3/genetics ; Receptor, Fibroblast Growth Factor, Type 3/metabolism
    Chemical Substances Polysaccharides ; FGFR3 protein, human (EC 2.7.10.1) ; Receptor, Fibroblast Growth Factor, Type 3 (EC 2.7.10.1)
    Language English
    Publishing date 2024-01-18
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 60-7
    ISSN 1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbagen.2024.130565
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.247: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Site-specific glycosylation analysis of epidermal growth factor receptor 2 (ErbB2): exploring structure and function toward therapeutic targeting.

    Fujitani, Naoki / Uehara, Yasuaki / Ariki, Shigeru / Hashimoto, Ukichiro / Mukai, Jo / Hasegawa, Yoshihiro / Takahashi, Motoko

    Glycobiology

    2023  Volume 34, Issue 3

    Abstract: Glycans found on receptor tyrosine kinases (RTKs) have emerged as promising targets for cancer chemotherapy, aiming to address issues such as drug resistance. However, to effectively select the target glycans, it is crucial to define the structure and ... ...

    Abstract Glycans found on receptor tyrosine kinases (RTKs) have emerged as promising targets for cancer chemotherapy, aiming to address issues such as drug resistance. However, to effectively select the target glycans, it is crucial to define the structure and function of candidate glycans in advance. Through mass spectrometric analysis, this study presents a "glycoform atlas" of epidermal growth factor receptor 2 (ErbB2), an RTK targeted for the treatment of ErbB2-positive cancers. Our analysis provides an in-depth and site-specific glycosylation profile, including both asparagine- and serine/threonine-linked glycosylation. Molecular dynamics simulations of N-glycosylated ErbB2 incorporating the identified glycan structures suggested that the N-glycan at N124 on the long flexible loop in the N-terminal region plays a role in stabilizing the ErbB2 structure. Based on the model structures obtained from the simulations, analysis employing an ErbB2 mutant deficient in N-glycosylation at N124 exhibited a significantly shorter intracellular half-life and suppressed autophosphorylation compared to wild-type ErbB2. Moreover, a structural comparison between the N-glycosylated forms of ErbB2 and its structurally homologous receptor, epidermal growth factor receptor (EGFR), demonstrated distinct variations in the distribution and density of N-glycans across these two molecules. These findings provide valuable insights into the structural and functional implications of ErbB2 glycosylation and will contribute to facilitating the establishment of glycan-targeted therapeutic strategies for ErbB2-positive cancers.
    MeSH term(s) Humans ; Glycosylation ; Phosphorylation ; Neoplasms ; Polysaccharides/metabolism
    Chemical Substances Polysaccharides
    Language English
    Publishing date 2023-12-16
    Publishing country England
    Document type Journal Article
    ZDB-ID 1067689-2
    ISSN 1460-2423 ; 0959-6658
    ISSN (online) 1460-2423
    ISSN 0959-6658
    DOI 10.1093/glycob/cwad100
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3150: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: N-glycosylation regulates MET processing and signaling.

    Saitou, Atsushi / Hasegawa, Yoshihiro / Fujitani, Naoki / Ariki, Shigeru / Uehara, Yasuaki / Hashimoto, Ukichiro / Saito, Atsushi / Kuronuma, Koji / Matsumoto, Kunio / Chiba, Hirofumi / Takahashi, Motoko

    Cancer science

    2022  Volume 113, Issue 4, Page(s) 1292–1304

    Abstract: MET, the receptor for the hepatocyte growth factor (HGF), is strongly associated with resistance to tyrosine kinase inhibitors, key drugs that are used in the therapy of non-small cell lung cancer. MET contains 11 potential N-glycosylation sites, but the ...

    Abstract MET, the receptor for the hepatocyte growth factor (HGF), is strongly associated with resistance to tyrosine kinase inhibitors, key drugs that are used in the therapy of non-small cell lung cancer. MET contains 11 potential N-glycosylation sites, but the site-specific roles of these N-glycans have not been elucidated. We report herein that these N-glycans regulate the proteolytic processing of MET and HGF-induced MET signaling, and that this regulation is site specific. Inhibitors of N-glycosylation were found to suppress the processing and trafficking of endogenous MET in H1975 and EBC-1 lung cancer cells and exogenous MET in CHO-K1 cells. We purified the recombinant extracellular domain of human MET and determined the site-specific N-glycan structures and occupancy using mass spectrometry. The results indicated that most sites were fully glycosylated and that the dominant population was the complex type. To examine the effects of the deletion of N-glycans of MET, we prepared endogenous MET knockout Flp-In CHO cells and transfected them with a series of N-glycan-deletion mutants of MET. The results showed that several N-glycans are implicated in the processing of MET. The findings also suggested that the N-glycans of the SEMA domain of MET positively regulate HGF signaling, and the N-glycans of the region other than the SEMA domain negatively regulate HGF signaling. Processing, cell surface expression, and signaling were significantly suppressed in the case of the all-N-glycan-deletion mutant. The overall findings suggest that N-glycans of MET affect the status and the function of the receptor in a site-specific manner.
    MeSH term(s) Animals ; Carcinoma, Non-Small-Cell Lung ; Cricetinae ; Cricetulus ; Glycosylation ; Hepatocyte Growth Factor/metabolism ; Humans ; Lung Neoplasms/drug therapy ; Proto-Oncogene Proteins c-met
    Chemical Substances Hepatocyte Growth Factor (67256-21-7) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1)
    Language English
    Publishing date 2022-02-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 2115647-5
    ISSN 1349-7006 ; 1349-7006
    ISSN (online) 1349-7006
    ISSN 1349-7006
    DOI 10.1111/cas.15278
    Database MEDical Literature Analysis and Retrieval System OnLINE

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