Site-specific N-glycosylation of integrin α2 mediates collagen-dependent cell survival

Yen-Lin Huang; Ching-Yeu Liang; Vera Labitzky; Danilo Ritz; Tiago Oliveira; Cécile Cumin; Manuela Estermann; Tobias Lange; Arun V Everest-Dass; Francis Jacob

doi:10.1016/j.isci.2021.103168

Site-specific N-glycosylation of integrin α2 mediates collagen-dependent cell survival

iScience. 2021 Sep 25;24(10):103168. doi: 10.1016/j.isci.2021.103168. eCollection 2021 Oct 22.

Authors

Affiliations

¹ Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, Hebelstrasse 20, Basel 4031, Switzerland.
² Institute of Anatomy and Experimental Morphology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg20246, Germany.
³ Proteomics Core Facility, Biozentrum, University of Basel, Basel4056, Switzerland.
⁴ Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast, QLD4222, Australia.
⁵ Adolphe Merkle Institute, University of Fribourg, Fribourg1700, Switzerland.

Abstract

Integrin 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.

Keywords: Cancer; Cell biology; Proteomics.