On the trail of the glycan codes stored in cancer-related cell adhesion proteins

Hoja-Łukowicz, Dorota; Przybyło, Małgorzata; Duda, Małgorzata; Pocheć, Ewa; Bubka, Monika

doi:10.1016/j.bbagen.2016.08.007

Cited by 25 publications

(27 citation statements)

References 267 publications

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“…As it was mentioned in Section 2, N -glycosylation of irisin is crucial to its secretion and the browning of adipocytes (Figure 2), and it seems possible that N -glycans also affect other activities of irisin. Future studies should be aimed at determining other glycosylation-dependent irisin functions and potential glycosylation changes that occur in pathological conditions, because numerous studies have demonstrated that glycosylation of different proteins is subject to change, mainly in carcinogenesis [95,96] and inflammation [97]. The detailed analysis of irisin glycosylation patterns and the effects of this post-translational modification on irisin actions are also crucial in the context of prophylactic and therapeutic uses of irisin.…”

Section: Discussionmentioning

confidence: 99%

Irisin as a Multifunctional Protein: Implications for Health and Certain Diseases

2019

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Sedentary life style is considered to be an independent risk factor for many disorders, including development of type 2 diabetes, obesity, immune dysfunction, asthma, and neurological or coronary heart disease. Irisin is released from myocytes during physical activity, and acts as a link between muscles and other tissues and organs. This myokine is produced as a result of proteolytic cleavage of FNDC5 protein present in the membrane of myocytes. Secretion of irisin is regulated by N-linked oligosaccharides attached to the protein molecule. The two N-glycan molecules, which constitute a significant part of the irisin glycoprotein, regulate the browning of adipocytes, which is the most important function of irisin. A receptor specific for irisin has still not been discovered. In some tissues irisin probably acts via integrins, which are widely expressed transmembrane receptors. Many studies have confirmed the multifunctional role of irisin and the beneficial effects of this molecule on body homeostasis. Irisin reduces systemic inflammation, maintains the balance between resorption and bone formation, and modulates metabolic processes and the functioning of the nervous system. It suppresses the expression and release of pro-inflammatory cytokines in obese individuals and attenuates inflammation in adipose tissue. The impact of irisin on cancer cell proliferation, migration, and invasion has also been demonstrated in numerous studies, which proves its role in carcinogenesis. Owing to these pleiotropic and beneficial properties, irisin may be a potential option to prevent and treat civilization-related diseases which are, nowadays, considered to be the major health problems in Western societies.

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Section: Discussionmentioning

confidence: 99%

Irisin as a Multifunctional Protein: Implications for Health and Certain Diseases

2019

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“…1). An increasing body of evidence indicates that integrin N-glycans contribute to cell adhesion and migration probably by affecting integrin expression, internalization, and association with other cell surface molecules 5, 15, 16 . However, a direct connection between integrin N-glycans and activation-dependent ligand binding has been missing.…”

Section: Discussionmentioning

confidence: 99%

The importance of N-glycosylation on β3 integrin ligand binding and conformational regulation

Cai

Thinn

Wang

et al. 2017

Sci Rep

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N-glycosylations can regulate the adhesive function of integrins. Great variations in both the number and distribution of N-glycosylation sites are found in the 18 α and 8 β integrin subunits. Crystal structures of αIIbβ3 and αVβ3 have resolved the precise structural location of each N-glycan site, but the structural consequences of individual N-glycan site on integrin activation remain unclear. By site-directed mutagenesis and structure-guided analyses, we dissected the function of individual N-glycan sites in β3 integrin activation. We found that the N-glycan site, β3-N320 at the headpiece and leg domain interface positively regulates αIIbβ3 but not αVβ3 activation. The β3-N559 N-glycan at the β3-I-EGF3 and αIIb-calf-1 domain interface, and the β3-N654 N-glycan at the β3-β-tail and αIIb-calf-2 domain interface positively regulate the activation of both αIIbβ3 and αVβ3 integrins. In contrast, removal of the β3-N371 N-glycan near the β3 hybrid and I-EGF3 interface, or the β3-N452 N-glycan at the I-EGF1 domain rendered β3 integrin more active than the wild type. We identified one unique N-glycan at the βI domain of β1 subunit that negatively regulates α5β1 activation. Our study suggests that the bulky N-glycans influence the large-scale conformational rearrangement by potentially stabilizing or destabilizing the domain interfaces of integrin.

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“…Another intriguing observation is that Gal-Nab1 does not modulate in the same way the responses of Jurkat cells and primary T cells stimulated by extra-cellular gal-9. To address this question, one needs to remember that Jurkat cells are malignant cells and therefore have a glycan profile on their plasma membrane which is not identical to primary CD3 + cells [ 48 ]. This might determine specific modalities of gal-9 interactions with Jurkat cells.…”

Section: Discussionmentioning

confidence: 99%

Characterization of neutralizing antibodies reacting with the 213-224 amino-acid segment of human galectin-9

et al. 2018

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Extra-cellular galectin-9 (gal-9) is an immuno-modulatory protein with predominant immunosuppressive effects. Inappropriate production of gal-9 has been reported in several human malignancies and viral diseases like nasopharyngeal, pancreatic and renal carcinomas, metastatic melanomas and chronic active viral hepatitis. Therefore therapeutic antibodies neutralizing extra-cellular gal-9 are expected to contribute to immune restoration in these pathological conditions. Two novel monoclonal antibodies targeting gal-9 –Gal-Nab 1 and 2—have been produced and characterized in this study. We report a protective effect of Gal-Nab1 and Gal-Nab2 on the apoptotic cell death induced by gal-9 in primary T cells. In addition, they inhibit late phenotypic changes observed in peripheral T cells that survive gal-9-induced apoptosis. Gal-Nab1 and Gal-Nab2 bind nearly identical, overlapping linear epitopes contained in the 213–224 amino-acid segments of gal-9. Nevertheless, they have some distinct functional characteristics suggesting that their three-dimensional epitopes are distinct. These differences are best demonstrated when gal-9 is applied on Jurkat cells where Gal-Nab1 is less efficient than Gal-Nab2 in the prevention of apoptotic cell death. In addition, Gal-Nab1 stimulates non-lethal phosphatidylserine translocation at the plasma membrane and calcium mobilization triggered by gal-9 in these cells. Both Gal-Nab1 and 2 cross-react with murine gal-9. They bind its natural as well as its recombinant form. This cross-species recognition will be an advantage for their assessment in pre-clinical tumor models.

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On the trail of the glycan codes stored in cancer-related cell adhesion proteins

Cited by 25 publications

References 267 publications

Irisin as a Multifunctional Protein: Implications for Health and Certain Diseases

Irisin as a Multifunctional Protein: Implications for Health and Certain Diseases

The importance of N-glycosylation on β3 integrin ligand binding and conformational regulation

Characterization of neutralizing antibodies reacting with the 213-224 amino-acid segment of human galectin-9

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