Research Highlights

Cancer cell migration: A complex tetraspanin story

Schematic diagram showing interrelationship between 31 and CD151 during integrin maturation. Association with CD151 is required for recruitment of 31-CD151 to tetraspanin-enriched microdomains. © 2008 by the American Society for Biochemistry and Molecular Biology.

N-glycosylation affects integrin's ability to interact with other proteins in the extracellular matrix, and thus can alter the migration and adhesion of both normal and cancer cells. Tetraspanins are transmembrane proteins that form stoichiometric complexes with integrins and modulate their function. The tetraspanin CD151 has been shown to regulate the function of laminin-binding integrins including 31, 61 and 64. Writing in the Journal of Biological Chemistry, Baldwin et al. delineate further the functional consequences of CD151–31 integrin complex formation.

The authors depleted CD151 in breast cancer cells and noticed that the glycosylation of the 3 integrin subunit was altered compared to wild-type cells. Moreover, incubating the depleted cancer cells with N-glycan-maturation inhibitors induced a change in early integrin biosynthesis. Importantly, glycosylation was not altered in other proteins within tetraspanin-enriched microdomains, such as CD63 and CD82, indicating that CD151 must specifically regulate the formation of complex 31 integrin N-glycans. Using various CD151 mutants, Baldwin et al. found that, as well as directly interacting with 31 integrin, the tetraspanin needed to be both glycosylated and palmitoylated to have activity towards the integrin.

The authors analyzed the glycans using lectin binding assays and showed that CD151 depletion caused specific defects in the formation of 31 N-glycans, including a decrease in 1-2 fucosylation of galactose residues. Next, Baldwin et al. analyzed the migration of normal, CD151-depleted and CD151 glycosylation-deficient cancer cells. Whereas CD151-depleted breast cancer cells displayed strongly diminished migration towards laminin-332, migration towards fibronectin was near normal. Notably, CD151 glycosylation was also required for migration, as cells carrying unglycosylated CD151 showed the same phenotype as the depleted cells.

The results of this study give an insight into how cancer cell migration is modulated by a network of protein-glycan interactions. It will be interesting to pinpoint the structural details by which CD151 N-glycans aid 31 integrin glycosylation, and how tetraspanin–integrin complex glycans interact with laminin to promote cancer cell migration.

Author: Mirko von Elstermann