Ras oncogene directs expression of a differentially sialylated, functionally altered β1 integrin

Abstract

Intense investigation has centered on understanding the regulation of integrin cell adhesion receptors. In the present study, we propose that variant N-glycosylation represents an important mechanism for regulation of beta1, but not beta3 or beta5 integrins. We find that expression of oncogenic ras in HD3 colonocytes causes increased alpha2-6 sialylation of beta1 integrins, whereas expression of dominant-negative ras induces decreased alpha2-6 sialylation, relative to cells with wild-type ras. In contrast, neither beta3 nor beta5 integrins are alpha2-6 sialylated, regardless of the state of ras activation. Results from RT-PCR analyses suggest that differential integrin sialylation is due to a ras-dependent alteration in the expression of ST6Gal I, the enzyme that adds alpha2-6-linked sialic acids. Cells that express differentially sialylated beta1 integrins exhibit altered adhesion to collagen I (a beta1 ligand), but not to vitronectin (a beta3 or beta5 ligand). Similarly, the enzymatic removal of cell surface sialic acids from control cells alters binding to collagen, but not to vitronectin. Finally, using a cell-free receptor/ligand-binding assay, we show that purified, desialylated alpha1beta1 integrins have diminished collagen-binding capability, providing strong evidence that sialic acids play a causal role in regulating beta1 integrin function.

Differential expression of the α2,3-sialic acid residues in breast cancer is associated with metastatic potential

“…Many studies suggested that an increased cell surface sialic acid content in cancer cells is caused by up-regulating of sialyltransferase (20)(21)(22)(23)(24) and depended on the mrnA levels of sialyltransferase gene (25). In breast cancer, the sialyltransferase (α2,3-st), is mainly responsible for catalyzing sialic acid to form α2,3-sialic acid residues (26).…”

B4GALNT3 Expression Predicts a Favorable Prognosis and Suppresses Cell Migration and Invasion via β1 Integrin Signaling in Neuroblastoma

“…For example, GnT-V, GnT-III, ST6GalNAc I, and ST6Gal-I directly modify carbohydrate structures on ␤ 1 integrin and affect integrin activity. [33][34][35][36] These changes in N-glycosylation 33,37 or O-glycosylation 36 of ␤ 1 integrin lead to altered cell morphologic features and behavior. B4GALNT3 modifies N-and O-glycans decorated with GlcNAc in vitro.…”

β1,4-N-Acetylgalactosaminyltransferase III Enhances Malignant Phenotypes of Colon Cancer Cells

“…GnT-V, GnT-III, ST6GalNAc I, and ST6Gal-I were found to directly modify carbohydrate structures on h1-integrin and affect integrin activity (8)(9)(10)(11). These changes in Nglycosylation (8,30) or O-glycosylation (11) of h1-integrin lead to altered cell morphology and behavior. Furthermore, GnT-III was found to modify carbohydrates on epidermal growth factor receptor and inhibit ERK-mediated neurite outgrowth in PC12 cells (31).…”