Abstract
SummaryIntegrin alpha 2 (ITGA2) promotes cancer metastasis through selective adhesion to ECM proteins; however, the specific contribution of integrin glycosylation remains uncertain. We provide evidence that ITGA2 is a highly glycosylated transmembrane protein expressed in ovarian cancer tissue and cell lines. In-depth glycoproteomics identified predominant N- and O-glycosylation sites harboring substantially divergent ITGA2 glycosylation profiles. Generated putative ITGA2 N-glycosite mutants halted collagen and laminin binding and cells lacking N-glycosylated ITGA2 were marginally adherent to collagen, likely associated with its enhanced proteasome degradation through poly-ubiquitination. Proteomic and enrichment pathway analysis revealed increased cellular apoptosis and collagen organization in non-glycosylated ITGA2 mutant cells. Moreover, we provide evidence that ITGA2-specific sialylation is involved in selective cell-ECM binding. These results highlight the importance of glycans in regulating ITGA2 stability and ligand binding capacity which in turn modulates downstream focal adhesion and promotes cell survival in a collagen environment.
Highlights
Protein glycosylation is one of the most common post-translational modifications found in all domains of life
We provide evidence that Integrin alpha 2 (ITGA2) is a highly glycosylated transmembrane protein expressed in ovarian cancer tissue and cell lines
ITGA2 is a highly abundant cell surface glycoprotein on ovarian cancer cells derived from tissue and ascites We have previously suggested a new route of peritoneal dissemination through the interaction of integrin alpha 2 with collagen I and III (Huang et al, 2020) usually enriched in the omental tumor of ovarian cancer patients (Pearce et al, 2018)
Summary
Protein glycosylation is one of the most common post-translational modifications found in all domains of life. Glycosylation plays crucial biological roles in protein folding and quality control, protein trafficking, and secretion as well as ligand recognition (Moremen et al, 2012). As glycan structures are highly diverse and altered in response to various biological processes such as cancer-associated cell survival, adhesion, and migration, there is a need to understand how glycosylation is regulated through a repertoire of glycosyltransferases and glycan-modifying enzymes along the biosynthetic pathway (Narimatsu et al, 2019). Recent advances in mass spectrometry-based analytical methodologies offer comprehensive glycan profiling allowing to better understand the contribution of glycosylation to biological regulation in specific cellular transitions and disease states (Moremen et al, 2012). The function of site-specific glycosylation of a particular protein in a functional context remains one of the major challenges in the field of glycobiology
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