Sialylation of 1 Integrins Blocks Cell Adhesion to Galectin-3 and Protects Cells against Galectin-3-induced Apoptosis

189

159

The glycosyltransferase, ST6Gal-I, adds sialic acid in an ␣2-6 linkage to the N-glycans of membrane and secreted glycoproteins. Up-regulation of ST6Gal-I occurs in many cancers, including colon carcinoma, and correlates with metastasis and poor prognosis. However, mechanisms by which ST6Gal-I facilitates tumor progression remain poorly understood due to limited knowledge of enzyme substrates. Herein we identify the death receptor, Fas (CD95), as an ST6Gal-I substrate, and show that ␣2-6 sialylation of Fas confers protection against Fas-mediated apoptosis. Intriguingly, differences in ST6Gal-I activity do not affect the function of DR4 or DR5 death receptors upon treatment with TRAIL, implicating a selective effect of ST6Gal-I on the Fas receptor. Using ST6Gal-I knockdown and forced overexpression colon carcinoma cell models, we find that ␣2-6 sialylation of Fas prevents apoptosis stimulated by FasL as well as the Fas-activating antibody, CH11, as evidenced by decreased activation of caspases 8 and 3. We also show that ␣2-6 sialylation of Fas does not alter the binding of CH11, but rather inhibits the capacity of Fas to induce apoptosis by blocking the association of FADD with Fas cytoplasmic tails, an event that initiates death-inducing signaling complex formation. Furthermore, ␣2-6 sialylation of Fas inhibits Fas internalization, which is required for apoptotic signaling. Although dysregulated Fas activity is a well known mechanism through which tumors evade apoptosis, the current study is the first to link Fas insensitivity to the actions of a specific sialyltransferase. This finding establishes a new paradigm by which death receptor function is impaired for the self-protection of tumors against apoptosis.

Section: Discussionmentioning

confidence: 99%

Sialylation of the Fas Death Receptor by ST6Gal-I Provides Protection against Fas-mediated Apoptosis in Colon Carcinoma Cells

Swindall

Bellis

2011

189

159

“…The finding that ␤-integrin is among the CvGal1 ligands on the hemocyte surface is intriguing, because in mammals this transmembrane signaling glycoprotein is not only a recognized galectin ligand (56) but is also pivotal in cell activation processes (57,58). The binding of galectins to the cell surface can form multivalent complexes (lattices) with cell surface glycoconjugate, and deliver a variety of intracellular signals to modulate cell activation, differentiation, and survival (59).…”

Section: Discussionmentioning

confidence: 99%

The Galectin CvGal1 from the Eastern Oyster (Crassostrea virginica) Binds to Blood Group A Oligosaccharides on the Hemocyte Surface*

Feng

Ghosh

Amin

et al. 2013

120

Background:The carbohydrate specificity of the oyster galectin CvGal1 for endogenous and exogenous glycans was unresolved. Results: CvGal1 recognizes blood group A tetrasaccharides on oyster hemocytes, which are absent on the surface of the P. marinus parasite. Conclusion: Oyster hemocytes and P. marinus display structurally distinct ligands for CvGal1. Significance: Galectins may function as pattern recognition receptors by binding microbial glycans structurally different from endogenous ligands.

“…N-Glycans are required for the activation but not for the localization of gp130 in NECs (64). Sialylation on the non-reducing terminus of N-glycans of ␣5␤1-integrin plays an important role in cell adhesion (65). Alterations of N-glycans on integrins could also regulate their cis interactions with membrane-associated proteins, including the epidermal growth factor receptor (66,67).…”

Section: ␤1-integrin Up-regulation By Growth Factors In Neural Stem Cmentioning

confidence: 99%

Involvement of β1-Integrin Up-regulation in Basic Fibroblast Growth Factor- and Epidermal Growth Factor-induced Proliferation of Mouse Neuroepithelial Cells

Suzuki

Yanagisawa

Yagi

et al. 2010

In neural stem cells, basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) promote cell proliferation and self-renewal. In the bFGF-and EGF-responsive neural stem cells, ␤1-integrin also plays important roles in crucial cellular processes, including proliferation, migration, and apoptosis. The cross-talk of the signaling pathways mediated by these growth factors and ␤1-integrin, however, has not been fully elucidated. Here we report a novel molecular mechanism through which bFGF or EGF promotes the proliferation of mouse neuroepithelial cells (NECs). In the NECs, total ␤1-integrin expression levels and proliferation were dose-dependently increased by bFGF but not by EGF. EGF rather than bFGF strongly induced the increase of ␤1-integrin localization on the NEC surface. bFGF-and EGF-induced ␤1-integrin up-regulation and proliferation were inhibited after treatment with a mitogen-activated protein kinase kinase inhibitor, U0126, which indicates the dependence on the mitogen-activated protein kinase pathway. Involvement of ␤1-integrin in bFGF-and EGF-induced proliferation was confirmed by the finding that NEC proliferation and adhesion to fibronectin-coated dishes were inhibited by knockdown of ␤1-integrin using small interfering RNA. On the other hand, apoptosis was induced in NECs treated with RGD peptide, a small ␤1-integrin inhibitor peptide with the Arg-Gly-Asp motif, but it was independent of ␤1-integrin expression levels. Those results suggest that regulation of ␤1-integrin expression/localization is involved in cellular processes, such as proliferation, induced by bFGF and EGF in NECs. The mechanism underlying the proliferation through ␤1-integrin would not be expected to be completely identical, however, for bFGF and EGF.Neural stem cells (NSCs) 3 are defined as undifferentiated neural cells with a high potential for proliferation and the capacity for self-renewal with retention of multipotency (1-4). During development, NSCs have the capability to generate brain-forming cells, such as neurons, astrocytes, and oligodendrocytes. The application of NSCs to cell-based transplantation is a very attractive and promising strategy for regenerative and restorative medicine (5-7).The fate of NSCs (self-renewal, proliferation, differentiation, survival, and death) is regulated by intracellular programs mediated by a number of transcription factors or epigenetic modifications, including DNA methylation, histone modification, and non-coding RNA expression (8 -11). Furthermore, the signaling pathways of various growth factors, the extracellular matrix, and cell adhesion molecules present in specific microenvironments or niche in NSCs are also known to play important roles in maintenance of the stem cell population (12-18). In particular, basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) are primary mitogens to promote proliferation of NSCs through the mitogen-activated protein kinase (MAPK) pathway in vitro (19 -22). The responses of NSCs to those growth factors are thought to ...