The Bisecting GlcNAc on <i>N</i>-Glycans Inhibits Growth Factor Signaling and Retards Mammary Tumor Progression

Song, Yinghui; Aglipay, Jason A.; Bernstein, Joshua; Goswami, Sumanta; Stanley, Pamela

doi:10.1158/0008-5472.can-09-2719

Cited by 94 publications

(81 citation statements)

References 45 publications

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“…6). Similarly, glycosylation with the bisecting GlcNAc on N-glycans inhibits mammary tumor progression (45). Our preliminary data also revealed that a sialic acid-containing glycolipid, SSEA4, is up-regulated in the TKI-resistant mutants of lung cancer cell lines, compared with the cells with wild-type EGFR (Fig.…”

Section: Discussionsupporting

confidence: 59%

Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

Yen

Liu²,

Chen³

et al. 2015

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

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Epidermal growth factor receptor (EGFR) is a heavily glycosylated transmembrane receptor tyrosine kinase. Upon EGF-binding, EGFR undergoes conformational changes to dimerize, resulting in kinase activation and autophosphorylation and downstream signaling. Tyrosine kinase inhibitors (TKIs) have been used to treat lung cancer by inhibiting EGFR phosphorylation. Previously, we demonstrated that EGFR sialylation suppresses its dimerization and phosphorylation. In this report, we further investigated the effect of sialylation on the phosphorylation profile of EGFR in TKIsensitive and TKI-resistant cells. Sialylation was induced in cancer progression to inhibit the association of EGFR with EGF and the subsequent autophosphorylation. In the absence of EGF the TKIresistant EGFR mutant (L858R/T790M) had a higher degree of sialylation and phosphorylation at Y1068, Y1086, and Y1173 than the TKI-sensitive EGFR. In addition, although sialylation in the TKIresistant mutants suppresses EGFR tyrosine phosphorylation, with the most significant effect on the Y1173 site, the sialylation effect is not strong enough to stop cancer progression by inhibiting the phosphorylation of these three sites. These findings were supported further by the observation that the L858R/T790M EGFR mutant, when treated with sialidase or sialyltransferase inhibitor, showed an increase in tyrosine phosphorylation, and the sensitivity of the corresponding resistant lung cancer cells to gefitinib was reduced by desialylation and was enhanced by sialylation.E pidermal growth factor receptor (EGFR), one of the most studied receptor tyrosine kinases, is a drug target for cancer therapy, because its kinase activity correlates with tumorigenicity (1). Under normal conditions, EGFR forms dimers upon ligand binding and induces kinase activation (2-6). The conformational change of EGFR from tethered to extended form induced by ligand binding involves the exposure of the interface, followed by dimerization, activation, and autophosphorylation (7). The phosphorylation code of EGFR determines the propensity of the downstream signaling network to regulate cell proliferation, survival, migration, and angiogenesis (8, 9).In a significant fraction of patients with nonsmall cell lung cancer (NSCLC), especially patients in Asia and those with the adenocarcinoma subtype, mutations in the kinase domain of EGFR cause constitutive activation and have been identified as an important factor in EGFR dysregulation (10, 11). Particularly, mutation from leucine to arginine at position 858 (L858R) and, less significantly, deletion of exon 19 that eliminates four amino acids (LREA) account for ∼90% of the mutations involved in the constitutive activation of EGFR. These mutations are commonly found in patients with increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib (12-14). However, most patients with such mutations show resistance within months after TKI therapy, and >50% of them develop a second EGFR mutation, T790M, which confers TKI resi...

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Section: Discussionsupporting

confidence: 59%

Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

Yen

Liu²,

Chen³

et al. 2015

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

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“…Sensitivity to EGF and TGFβ cytokines was rescued by hexosamine supplementation with UDP-GlcNAc or by GnT-V expression, implying that remodelling of N-glycans in tumour cells is sensitive to metabolism 161 . Accordingly, the decrease of galectin lattice interactions induced by the addition of bisecting GlcNAc N-glycans counterbalances the highly branched N-glycosylation of EGFR and PDGFR, restraining its downstream signalling and in this way retarding mammary tumour progression 166 . GnT-III overexpression reduces the ability of EGF to bind to its receptor, blocking EGFR-mediated ERK phosphorylation and increasing EGFR endocytosis 167 .…”

Section: Tumour Editingmentioning

confidence: 99%

Glycosylation in cancer: mechanisms and clinical implications

2015

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Despite recent progress in understanding the cancer genome, there is still a relative delay in understanding the full aspects of the glycome and glycoproteome of cancer. Glycobiology has been instrumental in relevant discoveries in various biological and medical fields, and has contributed to the deciphering of several human diseases. Glycans are involved in fundamental molecular and cell biology processes occurring in cancer, such as cell signalling and communication, tumour cell dissociation and invasion, cell-matrix interactions, tumour angiogenesis, immune modulation and metastasis formation. The roles of glycans in cancer have been highlighted by the fact that alterations in glycosylation regulate the development and progression of cancer, serving as important biomarkers and providing a set of specific targets for therapeutic intervention. This Review discusses the role of glycans in fundamental mechanisms controlling cancer development and progression, and their applications in oncology.

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“…The addition of this branch prevents all further branching and elongation of the glycan structures. Overexpression of GnT-III retards tumor growth and metastases 51 and antagonizes the activity of Mgat5. 52 In addition, it is thought that GnT-III is capable of regulating intracellular signaling, but these observations require further investigation.…”

Section: N-glycosylationmentioning

confidence: 99%

The Impact of the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway on Glycosylation

Mehta¹

2017

GBI

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Glycan changes, in addition to being traditional mediators of protein quality control, cell signaling, and metabolism, are intimately linked to the progression of cancer and can potentially act as novel therapeutic and diagnostic targets. Despite advances in our understanding that glycosylation plays a key role in protein folding, maturation, and function, there is only limited understanding of the interconnected nature of glycan alterations to endoplasmic reticulum stress, the unfolded protein response, and the development of cancer. This review aims to highlight the interdependence of these pathways and the way they feed into each other to maintain protein quality control, regulate key survival mechanisms, and promote cell viability.

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The Bisecting GlcNAc on N-Glycans Inhibits Growth Factor Signaling and Retards Mammary Tumor Progression

Cited by 94 publications

References 45 publications

Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

Glycosylation in cancer: mechanisms and clinical implications

The Impact of the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway on Glycosylation

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