Notch Signaling in Normal and Disease States: Possible Therapies Related to Glycosylation

Rampal, Raajit K.; Luther, Kelvin B.; Haltiwanger, Robert S.

doi:10.2174/156652407780831593

Cited by 88 publications

(72 citation statements)

References 162 publications

(258 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The EGF-like repeats in the extracellular domain of Notch and other vertebrate proteins are modified by O-fucose and O-glucose glycans (Rampal et al 2007;Stanley and Okajima 2010), as well as O-GlcNAc (Matsuura et al 2008; Fig. 1).…”

Section: O-glycosylationmentioning

confidence: 99%

Golgi Glycosylation

Stanley

2011

Cold Spring Harbor Perspectives in Biology

362

283

View full text Add to dashboard Cite

Section: O-glycosylationmentioning

confidence: 99%

Golgi Glycosylation

Stanley

2011

Cold Spring Harbor Perspectives in Biology

362

283

View full text Add to dashboard Cite

“…It plays essential roles in multiple stages of metazoan development and tissue renewal. Its dysregulation is participated in a number of human diseases such as cancers and developmental disorders 10, 11.…”

Section: Notch Signalingmentioning

confidence: 99%

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

et al. 2016

View full text Add to dashboard Cite

The role of Notch pathway in tumorigenesis is highly variable. It can be tumor suppressive or pro‐oncogenic, typically depending on the cellular context. Squamous cell carcinoma (SCC) is a cancer of the squamous cell, which can occur in diverse human tissues. SCCs are one of the most frequent human malignancies for which the pathologic mechanisms remain elusive. Recent genomic analysis of diverse SCCs identified marked levels of mutations in NOTCH1, implicating Notch signaling pathways in the pathogenesis of SCCs. In this review, evidences highlighting NOTCH's role in different types of SCCs are summarized. Moreover, based on accumulating structural information of the NOTCH receptor, the functional consequences of NOTCH1 gene mutations identified from diverse SCCs are analyzed, emphasizing loss of function of Notch in these cancers. Finally, we discuss the convergent view on an intriguing possibility that Notch may function as tumor suppressor in SCCs across different tissues. These mechanistic insights into Notch signaling pathways will help to guide the research of SCCs and development of therapeutic strategies for these cancers.

show abstract

“…1 and 2, although larger portions of mN1 (e.g. EGF [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] were also analyzed to confirm that utilization of glycosylation sites was not affected by the size of the fragment being analyzed. Modified peptides were identified by neutral loss of the O-glucose saccharides upon low energy CID fragmentation.…”

Section: Mouse Notch1 Is Extensively Modified With O-glucose Inmentioning

confidence: 99%

“…Defects in Notch signaling have been implicated in a number of human diseases, including several forms of cancer, vascular defects such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (4 -6), multiple sclerosis (6), and a number of developmental syndromes (4,(7)(8)(9)(10). The canonical Notch signaling pathway is initiated by the interaction of Notch with its ligand on an apposed cell.…”

mentioning

confidence: 99%

O-Glucose Trisaccharide Is Present at High but Variable Stoichiometry at Multiple Sites on Mouse Notch1

Rana¹,

Nita‐Lazar²,

Takeuchi

et al. 2011

Journal of Biological Chemistry

120

View full text Add to dashboard Cite

Notch activity is regulated by both O-fucosylation and O-glucosylation, and Notch receptors contain multiple predicted sites for both. Here we examine the occupancy of the predicted O-glucose sites on mouse Notch1 (mN1) using the consensus sequence C 1 XSXPC 2 . We show that all of the predicted sites are modified, although the efficiency of modifying O-glucose sites is site-and cell type-dependent. For instance, although most sites are modified at high stoichiometries, the site at EGF 27 is only partially glucosylated, and the occupancy of the site at EGF 4 varies with cell type. O-Glucose is also found at a novel, nontraditional consensus site at EGF 9. Based on this finding, we propose a revision of the consensus sequence for O-glucosylation to allow alanine N-terminal to cysteine 2: C 1 XSX(A/P)C 2 . We also show through biochemical and mass spectral analyses that serine is the only hydroxyamino acid that is modified with O-glucose on EGF repeats. The O-glucose at all sites is efficiently elongated to the trisaccharide Xyl-Xyl-Glc. To establish the functional importance of individual O-glucose sites in mN1, we used a cell-based signaling assay. Elimination of most individual sites shows little or no effect on mN1 activation, suggesting that the major effects of O-glucose are mediated by modification of multiple sites. Interestingly, elimination of the site in EGF 28, found in the Abruptex region of Notch, does significantly reduce activity. These results demonstrate that, like O-fucose, the O-glucose modifications of EGF repeats occur extensively on mN1, and they play important roles in Notch function.The Notch family of single-pass transmembrane receptors is essential for early metazoan development, activating the expression of many genes involved in cell differentiation and tissue morphogenesis (1-3). Defects in Notch signaling have been implicated in a number of human diseases, including several forms of cancer, vascular defects such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (4 -6), multiple sclerosis (6), and a number of developmental syndromes (4, 7-10). The canonical Notch signaling pathway is initiated by the interaction of Notch with its ligand on an apposed cell. Upon ligand binding, Notch undergoes presenilin-1-dependent proteolysis, releasing a soluble Notch intracellular domain, which enters the cell nucleus to interact directly with the transcription factors from the CSL family and regulate Notch target genes (2). There are four members of the Notch family in vertebrates (Notch1 to Notch4) interacting with several classes of Notch ligands: ligands of the DSL family (Delta-like 1, 3, and 4 and Jagged 1 and 2) (1) and newly characterized ligands without the DSL domain, such as DNER and MAGP-1 and -2 (11-13).The Notch proteins consist of a large extracellular domain (ECD), 5 a transmembrane region, and a large intracellular domain (1, 2, 14). The majority of the ECD consists of tandem epidermal growth factor-like (EGF) repeats (36 EGF repeats are ...

show abstract

Notch Signaling in Normal and Disease States: Possible Therapies Related to Glycosylation

Cited by 88 publications

References 162 publications

Golgi Glycosylation

Golgi Glycosylation

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

O-Glucose Trisaccharide Is Present at High but Variable Stoichiometry at Multiple Sites on Mouse Notch1

Contact Info

Product

Resources

About