Functional impact of glycosylation of LRIG1 on EGFR proteostasis in cancer

LRIG1, a membrane glycoprotein, has emerged as a significant stem cell marker and negative regulator of receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR). Glycosylation is a major post-translational modification, which plays a crucial role in protein function and stability. In cancer biology, abnormal glycosylation can contribute to pathogenesis, which can also serve as a biomarker in clinical setting. Here, we aimed to investigate the effects of glycosylation on LRIG1 functions. Through database analysis and experimental approaches, we focused on evolutionarily conserved glycosylation sites of LRIG1, particularly N74 in humans. We found that a mutation of the N74 glycosylation site (N74Q) enhances LRIG1's binding to EGFR and promotes EGFR degradation. Furthermore, we identified a naturally occurring splice variant of LRIG1 lacking the 72-bp exon 2, which includes the N74 site, that shows similar enhanced EGFR binding and degradation. Our findings suggest that the absence of glycosylation at N74 site enhances LRIG1-EGFR binding, providing an example of glycosylation negatively regulating protein-protein interaction. This mechanism provides insights into the importance of glycosylation deficiency in cancer biology.