Regulation of Cytokine Receptors by Golgi N-Glycan Processing and Endocytosis

  title={Regulation of Cytokine Receptors by Golgi N-Glycan Processing and Endocytosis},
  author={Emily A. Partridge and Christine Le Roy and Gianni M. Di Guglielmo and Judy Pawling and Pam Cheung and Maria Granovsky and Ivan Robert Nabi and Jeffrey L. Wrana and James W. Dennis},
  pages={120 - 124}
The Golgi enzyme β1,6 N-acetylglucosaminyltransferase V (Mgat5) is up-regulated in carcinomas and promotes the substitution of N-glycan with poly N-acetyllactosamine, the preferred ligand for galectin-3 (Gal-3). Here, we report that expression of Mgat5 sensitized mouse cells to multiple cytokines. Gal-3 cross-linked Mgat5-modified N-glycans on epidermal growth factor and transforming growth factor–β receptors at the cell surface and delayed their removal by constitutive endocytosis. Mgat5… 

Complex N-glycan and metabolic control in tumor cells.

The results suggest that complex N-glycans sensitize tumor cells to growth factors, and Mgat5 is required to balance responsiveness to growth and arrest cues downstream of metabolic flux.

Structural analysis of cytokine signaling modulators

It is suggested that present in a higher number the glycans with lower LacNAc multiplicity are able to establish lattice interactions with adequate avidity to stimulate cytokine signaling and tumor progression in a Mgat 5 null background.

N-Glycans in cancer progression.

A systems approach to cancer treatment where the surface distribution of receptors is targeted through metabolism and N-glycan branching to induce growth arrest is suggested.

Metabolic homeostasis and tissue renewal are dependent on beta1,6GlcNAc-branched N-glycans.

It is demonstrated that Mgat5(-/-) mouse embryonic fibroblasts (MEFs) display reduced sensitivity to anabolic cytokines and reduced glucose uptake and proliferation, and suggested that beta1,6GlcNAc-branched N-glycans promote sensitivity toAnabolic cytokine, and increase fat stores, tissue renewal, and longevity.

Galectin Binding to Mgat5-Modified N-Glycans Regulates Fibronectin Matrix Remodeling in Tumor Cells

The results demonstrate that fibronectin polymerization and tumor cell motility are regulated by galectin-3 binding to branched N-glycan ligands that stimulate focal adhesion remodeling, FAK and PI3K activation, local F-actin instability, and α5β1 translocation to fibrillar adhesions.

Assembly, organization and regulation of cell-surface receptors by lectin-glycan complexes.

In the present review, the data available on the assembly, hierarchical organization and regulation of conspicuous galectin-glycan complexes, and their implications in health and disease are summarized.

Adaptive Regulation at the Cell Surface by N‐Glycosylation

Computational modelling of the hexosamine/Golgi/lattice has provided new insight on cell surface adaptation in cancer and autoimmune disease.

VIP36 preferentially binds to core-fucosylated N-glycans: a molecular docking study

This fundamental approach with large scale docking of 165 carbohydrates suggests, that linked cargo-receptor apical transport may provide a path to epithelial polarization that may be modulated by core fucosylation.



Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation

It is demonstrated that a deficiency in β1,6 N-acetylglucosaminyltransferase V (Mgat5), an enzyme in the N-glycosylation pathway, lowers T-cell activation thresholds by directly enhancing TCR clustering.

Suppression of tumor growth and metastasis in Mgat5-deficient mice

The results indicate that inhibitors of MGAT5 might be useful in the treatment of malignancies by targeting their dependency on focal adhesion signaling for growth and metastasis.

Transforming Growth Factor β Up-regulates Expression of the N-Acetylglucosaminyltransferase V Gene in Mouse Melanoma Cells (*)

Results suggested that TGFβ caused changes in the sugar chains of proteins in melanoma cells by up-regulating GnT-V expression.

The her-2/neu oncogene stimulates the transcription of N-acetylglucosaminyltransferase V and expression of its cell surface oligosaccharide products

It is found that neu-transformed NIH3T3 cells have a threefold increase in GlcNAc-T V enzyme activity and increased β(1,6) branching on a specific set of glycoproteins.

The NH2 terminus of galectin-3 governs cellular compartmentalization and functions in cancer cells.

A structural role for the NH2 terminus leader motif of galectin-3 is suggested in determining its cellular targeting and biological functions independent of phosphorylation.

Reduced contact-inhibition and substratum adhesion in epithelial cells expressing GlcNAc-transferase V

The results suggest that beta 1-6GlcNAc branching of N-linked oligosaccharides contributes directly to relaxed growth controls and reduce substratum adhesion in premalignant epithelial cells.

Distinct endocytic pathways regulate TGF-β receptor signalling and turnover

It is demonstrated that TGF-β receptors internalize into both caveolin- and EEA1-positive vesicles and reside in both lipid raft and non-raft membrane domains, which regulates Smad activation and receptor turnover.

Characterization of the carbohydrate chains of the secreted form of the human epidermal growth factor receptor.

32 new complex-type glycans are characterized containing the Le(x), Le(Y), and sialyl-Le(x) determinants, the bloodgroup A and H antigens, as well as the ALe(Y) determinant.

Cbl–CIN85–endophilin complex mediates ligand-induced downregulation of EGF receptors

It is demonstrated that Cbl additionally regulates epidermal growth factor (EGF) receptor endocytosis and uses a mechanism that is functionally separable from the ubiquitin ligase activity of Cbl to mediate ligand-dependent downregulation of receptor tyrosine kinases.