Role of Glycans on Key Cell Surface Receptors That Regulate Cell Proliferation and Cell Death

Gao, Yin; Luan, Xue; Melamed, Jacob; Brockhausen, Inka

doi:10.3390/cells10051252

Cited by 33 publications

(28 citation statements)

References 170 publications

(233 reference statements)

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“…Sialic acid residues (sialosides) on the cell surface can mediate influenza virus binding and entry into the cell [ 6 ] as they are responsible for intermolecular interactions, particularly in host recognition during bacterial and viral infection [ 7 ]. EGFRs are heavily glycosylated transmembrane proteins with multiple sialic acid residues typically located at the terminal end of glycan structures [ 8 ]. Notably, EGFR has been demonstrated to be a co-receptor for viral infection [ 9 , 10 ] and to transduce signals relevant to virus entry [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

A Multiscale Molecular Dynamic Analysis Reveals the Effect of Sialylation on EGFR Clustering in a CRISPR/Cas9-Derived Model

Leong

Hsiao

Shie

2022

IJMS

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Bacterial and viral pathogens can modulate the glycosylation of key host proteins to facilitate pathogenesis by using various glycosidases, particularly sialidases. Epidermal growth factor receptor (EGFR) signaling is activated by ligand-induced receptor dimerization and oligomerization. Ligand binding induces conformational changes in EGFR, leading to clusters and aggregation. However, information on the relevance of EGFR clustering in the pattern of glycosylation during bacterial and viral invasion remains unclear. In this study, (1) we established CRISPR/Cas9-mediated GFP knock-in (EGFP-KI) HeLa cells expressing fluorescently tagged EGFR at close to endogenous levels to study EGF-induced EGFR clustering and molecular dynamics; (2) We studied the effect of sialylation on EGF-induced EGFR clustering and localization in live cells using a high content analysis platform and raster image correlation spectroscopy (RICS) coupled with a number and brightness (N&B) analysis; (3) Our data reveal that the removal of cell surface sialic acids by sialidase treatment significantly decreases EGF receptor clustering with reduced fluorescence intensity, number, and area of EGFR-GFP clusters per cell upon EGF stimulation. Sialylation appears to mediate EGF-induced EGFR clustering as demonstrated by the change of EGFR-GFP clusters in the diffusion coefficient and molecular brightness, providing new insights into the role of sialylation in EGF-induced EGFR activation; and (4) We envision that the combination of CRISPR/Cas9-mediated fluorescent tagging of endogenous proteins and fluorescence imaging techniques can be the method of choice for studying the molecular dynamics and interactions of proteins in live cells.

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Section: Introductionmentioning

confidence: 99%

A Multiscale Molecular Dynamic Analysis Reveals the Effect of Sialylation on EGFR Clustering in a CRISPR/Cas9-Derived Model

Leong

Hsiao

Shie

2022

IJMS

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“…More recently, we determined that ST6GAL1-mediated sialylation of EGFR prolongs downstream survival signaling by enhancing EGFR retention on the cell surface (24). It is well-known that N-glycans play seminal roles in modulating EGFR structure and signaling (71)(72)(73). For example, an N-glycan attached to Asn-579 is a central player in maintaining the autoinhibitory tether within the EGFR structure (74), and this N-glycan is a known target for sialylation by ST6GAL1 (75).…”

Section: Discussionmentioning

confidence: 99%

ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression

Chakraborty¹,

Bhalerao²,

Marciel³

et al. 2022

Preprint

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The role of aberrant glycosylation in pancreatic ductal adenocarcinoma (PDAC) remains an under-investigated area of research. In this study, we determined that the ST6GAL1 sialyltransferase, which adds α2,6-linked sialic acids to N-glycosylated proteins, is upregulated in patients with early-stage PDAC, and further increased in advanced disease. A tumor-promoting function for ST6GAL1 was elucidated using tumor xenograft models with human PDAC cells. Additionally, we developed a genetically-engineered mouse (GEM) with transgenic expression of ST6GAL1 in the pancreas, and found that mice with dual expression of ST6GAL1 and oncogenic KRASG12D have greatly accelerated PDAC progression and mortality compared with mice expressing KRASG12D alone. As ST6GAL1 imparts progenitor-like characteristics, we interrogated ST6GAL1’s role in acinar to ductal metaplasia (ADM), a process that fosters neoplasia by reprogramming acinar cells into ductal, progenitor-like cells. We confirmed that ST6GAL1 promotes ADM using multiple models including the 266-6 cell line, GEM-derived organoids and tissues, and an in vivo model of inflammation-induced ADM. EGFR is a key driver of ADM and is known to be activated by ST6GAL1-mediated sialylation. Importantly, EGFR activation was dramatically increased in acinar cells and organoids from mice with transgenic ST6GAL1 expression. These collective results highlight a novel glycosylation-dependent mechanism involved in early stages of pancreatic neoplasia.

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“…Cancer cells usually exhibit altered glycosylation, which is associated with defects in apoptosis [9]. Death receptors such as Fas and DR4/5 are glycoproteins which impact glycosylation during receptor expression, distribution, ligand-receptor interaction, and downstream signaling transduction [9]. Through binding to DR4/5, TRAIL triggers cell death through the extrinsic apoptotic pathway [65].…”

Section: Discussionmentioning

confidence: 99%

“…Cancer progression associated with abnormal glycosylation and these altered glycans regulate a series of pathological processes, including cell-cell interaction, cell adhesion, receptor activation, and signal transduction [8]. Due to the key role of glycosylation in protein expression and transport, ligand binding, and receptor signal transmission [9], the study of its involvement in signal pathway disorders and the development of new strategies to modify cell glycosylation have received significant attention. Recent research has indicated that glycosylation modifications are closely related to HCC, and the upregulation of galactosyltransferase expression was shown to be related to cancer metastasis [10].…”

Section: Introductionmentioning

confidence: 99%

Bisimidazolium Salt Glycosyltransferase Inhibitors Suppress Hepatocellular Carcinoma Progression In Vitro and In Vivo

et al. 2022

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Hepatocellular carcinoma is a leading cause of cancer death, and the disease progression has been related to glycophenotype modifications. Previously synthesized bisimidazolium salts (C20 and C22) have been shown to selectively inhibit the activity of glycosyltransferases in cultured cancer cell homogenates. The current study investigated the anticancer effects of C20/C22 and the possible pathways through which these effects are achieved. The therapeutic value of C20/C22 in terms of inhibiting cancer cell proliferation, metastasis, and angiogenesis, as well as inducing apoptosis, were examined with hepatic cancer cell line HepG2 and a xenograft mouse model. C20/C22 treatment downregulated the synthesis of SLex and Ley sugar epitopes and suppressed selectin-mediated cancer cell metastasis. C20/C22 inhibited HepG2 proliferation, induced cell-cycle arrest, increased intracellular ROS level, led to ER stress, and eventually induced apoptosis through the intrinsic pathway. Furthermore, C20/C22 upregulated the expressions of death receptors DR4 and DR5, substantially increasing the sensitivity of HepG2 to TRAIL-triggered apoptosis. In vivo, C20/C22 effectively inhibited tumor growth and angiogenesis in the xenograft mouse model without adverse effects on major organs. In summary, C20 and C22 are new promising anti-hepatic cancer agents with multiple mechanisms in controlling cancer cell growth, metastasis, and apoptosis, and they merit further development into anticancer drugs.

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Role of Glycans on Key Cell Surface Receptors That Regulate Cell Proliferation and Cell Death

Cited by 33 publications

References 170 publications

A Multiscale Molecular Dynamic Analysis Reveals the Effect of Sialylation on EGFR Clustering in a CRISPR/Cas9-Derived Model

A Multiscale Molecular Dynamic Analysis Reveals the Effect of Sialylation on EGFR Clustering in a CRISPR/Cas9-Derived Model

ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression

Bisimidazolium Salt Glycosyltransferase Inhibitors Suppress Hepatocellular Carcinoma Progression In Vitro and In Vivo

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