Abstract:
Epidermal growth factor receptor (EGFR) signaling plays an important role in proliferation and migration of normal and transformed cells. Upon binding to EGF, this receptor is endocytosed and confined in endosomes, where it continues to relay a signal cascade through adaptor proteins and their associated kinases, including growth factor receptor-bound protein 2 (Grb2) and mitogen-activated protein kinases (MAPKs). Galectin-3 is a chimeric type of glycan-binding protein, and has recently been reported to sense the presence of beta-glycosides complex type N-glycan in the cytoplasm when endosomes are damaged by intracellular membrane-disruptive substances.
Using three dimensional cultures of cancer cells, we found spontaneous formation of galectin-3 aggregates in centrally-located cells within the tumor spheroids, suggesting endosomal damage has occurred in those cells. This was probably triggered by hypoxia and oxidative stress that were developed in the cells. Enhanced sialyation on cell surface glycans is common in cancer cells, which can contribute to suppression of immune cell activation. Here, we found sialylation on EGFR prevents galectin-3-mediated suppression of endosome signaling: deficiency in EGFR sialylation resulting from CRISPR/CAS9-mediated knockout of SLC35A1 (CMP-Sialic Acid Transporter gene) in HeLa cells, caused heightened galectin-3-mediated suppression of EGF-EGFR signaling, as reflected by decreased interleukin-8 (IL-8) mRNA level. Moreover, we found that galectin-3 can decipher the glycan composition in damaged endosomes, thus modulating EGF-EGFR signaling endosome. We conclude a new role of intracellular glycan-galectin-3 aggregation, that regulates endosomal signaling.
Keywords – Galectin, Glycan, EGFR, endosome damage.
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