N-Glycosylation Regulates ADAM8 Processing and Activation

Srinivasan, Srimathi; Romagnoli, Mathilde; Bohm, Andrew; Sonenshein, Gail E.

doi:10.1074/jbc.m114.594242

Cited by 22 publications

(19 citation statements)

References 43 publications

(18 reference statements)

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“…82 The processing and activation of ADAM8 requires glycosylation at multiple sites, i.e., at Asn-67, Asn-91, Asn-436, and Asn-612. 83 This pattern of glycosylation was observed in estrogen receptor-negative but was not seen in estrogen receptorpositive breast cancer cells.…”

Section: Adam8mentioning

confidence: 89%

The ADAMs family of proteases as targets for the treatment of cancer

Mullooly

McGowan

Crown

et al. 2016

Cancer Biology & Therapy

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The ADAMs (a disintegrin and metalloproteases) are transmembrane multidomain proteins implicated in multiple biological processes including proteolysis, cell adhesion, cell fusion, cell proliferation and cell migration. Of these varied activities, the best studied is their role in proteolysis. However, of the 22 ADAMs believed to be functional in humans, only approximately a half possess matrix metalloproteinase (MMP)-like protease activity. In contrast to MMPs which are mostly implicated in the degradation of extracellular matrix proteins, the main ADAM substrates are the ectodomains of type I and type II transmembrane proteins. These include growth factor/cytokine precursors, growth factor/cytokine receptors and adhesion proteins. Recently, several different ADAMs, especially ADAM17, have been shown to play a role in the development and progression of multiple cancer types. Consistent with this role in cancer, targeting ADAM17 with either low molecular weight inhibitors or monoclonal antibodies was shown to have anticancer activity in multiple preclinical systems. Although early phase clinical trials have shown no serious side effects with a dual ADAM10/17 low molecular weight inhibitor, the consequences of long-term treatment with these agents is unknown. Furthermore, efficacy in clinical trials remains to be shown.

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Section: Adam8mentioning

confidence: 89%

The ADAMs family of proteases as targets for the treatment of cancer

Mullooly

McGowan

Crown

et al. 2016

Cancer Biology & Therapy

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“…This approach is still the most reliable method for obtaining detailed structural information about the protein-modifying carbohydrates as the protein-level heterogeneity, both in terms of site occupancy and the number of site-specific structures, represent exceptional challenges for analysis. However, information about protein and site-specific glycosylation is lost by this approach, so there is a growing need for routine glycopeptide analysis, as glycosylation has been implicated as a key player in cell-cell interactions, host/pathogen interactions, enzymatic processing, and even intracellular signaling (7)(8)(9)(10)(11)(12)(13). Studies have shown that glycosylation is species-, and tissuespecific, and can be altered by disease or physiological changes (14 -22).…”

mentioning

confidence: 99%

Tissue-Specific Glycosylation at the Glycopeptide Level

Medzihradszky

Kaasik

Chalkley

2015

Molecular & Cellular Proteomics

105

107

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This manuscript describes the enrichment and mass spectrometric analysis of intact glycopeptides from mouse liver, which yielded site-specific N-and O-glycosylation data for ϳ130 proteins. Incorporation of different sialic acid variants in both N-and O-linked glycans was observed, and the importance of using both collisional activation and electron transfer dissociation for glycopeptide analysis was illustrated. The N-glycan structures of predicted lysosomal, endoplasmic reticulum (ER), secreted and transmembrane proteins were compared. The data suggest that protein N-glycosylation differs depending on cellular location. The glycosylation patterns of several mouse liver and mouse brain glycopeptides were compared. Tissue-specific differences in glycosylation were observed between sites within the same protein: Some sites displayed a similar spectrum of glycan structures in both tissues, whereas for others no overlap was observed. We present comparative brain/liver glycosylation data on 50 N-glycosylation sites from 34 proteins and 13 O-glycosylation sites from seven proteins. Molecular

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“…Complex N-Glycosylation does not affect CD133 cell surface localization N-glycosylation is known to affect membrane protein localization [42][43][44][45]. We next examined the effects of swainsonine on cell surface localization of CD133.…”

Section: Resultsmentioning

confidence: 99%

Complex N‐glycan promotes CD133 mono‐ubiquitination and secretion

Shi

Yang

et al. 2019

FEBS Letters

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CD133 is a widely used cell surface marker of cancer stem cells that plays an important role in tumor initiation and metastasis. Increasing evidence shows that CD133 is secreted to the extracellular space. However, the underlying mechanisms of CD133 secretion remain largely unknown. In this study, we report that secreted CD133 has a complex‐type N‐glycosylation and is modified by beta1,6GlcNAc N‐glycan. We found that inhibition of CD133 complex‐type N‐glycosylation by swainsonine does not affect the membrane localization of CD133, but significantly reduces CD133 secretion and promotes its accumulation in early endosomes. Moreover, swainsonine reduces CD133 secretion by reducing its mono‐ubiquitination and inhibiting the interaction between CD133 and Tsg101. These findings reveal a new mechanism of glycosylation‐dependent secretion of CD133.

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N-Glycosylation Regulates ADAM8 Processing and Activation

Cited by 22 publications

References 43 publications

The ADAMs family of proteases as targets for the treatment of cancer

The ADAMs family of proteases as targets for the treatment of cancer

Tissue-Specific Glycosylation at the Glycopeptide Level

Complex N‐glycan promotes CD133 mono‐ubiquitination and secretion

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