Terminal alpha2-6 sialylation regulates beta1 integrin adhesion receptor function

Both beta-galactoside alpha2-6 sialyltransferase (ST6Gal-I) and its carbohydrate product, alpha2-6 sialic acid, are consistently up-regulated in many cancers including colon adenocarcinoma. Numerous in vivo and in vitro studies have linked up-regulated ST6Gal-I expression and/or activity with increased cellular adhesion, migration, and invasiveness, suggesting a causative role for ST6Gal-I in tumor progression. However, because ST6Gal-I's protein targets are unknown, the mechanisms of ST6Gal-I-mediated cellular phenotypic changes in human cancers remains unexplored.;Our work establishes beta1 integrin adhesion receptors as ST6Gal-I targets in both colon adenocarcinoma cells and maturing myeloid cells upon ras-mediated signaling cascade activation. Colonocytes expressing hypersialylated beta1 integrins in response to either constitutive-ras activation or stable ST6Gal-I expression alter adhesion and up-regulate migratory capacity on beta1 ligands including collagen and laminin. Similar to cell surface collagen-binding beta1 integrins, purified collagen-binding beta1 integrin activity is reduced by enzymatic removal of sialic acids. beta1 integrins from colon adenocarcinoma tissues, which carry high rates of ras mutations, are also hypersialylated compared to beta1 integrins from pair-matched normal epithelial tissues, suggesting that ras-directed changes in beta1 sialylation are one mechanism for the increased adhesive and migratory capacity of colon tumor cells. In contrast to colonocytes, myeloid cells differentiating along the monocyte/macrophage lineage employ a protein kinase C/ras/extracellular signal-related kinase signaling cascade to down-regulate ST6Gal-I, leading to expression of hyposialylated beta1 integrins with increased fibronectin-binding capacity. Purified fibronectin-binding beta1 integrins are activated by desialylation, recapitulating the increased fibronectin-binding capacity of myeloid cell surface beta1 receptors hyposialylated in response to protein kinase C/ras/extracellular signal-related kinase signaling.;Collectively, our work establishes glycosylation as a novel mechanism for ras-mediated integrin regulation. In contrast to rapid and transient integrin activation associated with intracellular ras-mediated signaling events, glycosylation may confer long-term changes in cell adhesion and/or motility, given that termination of the response would require integrin turnover. Hence, variant glycosylation, when compared with other mechanisms of integrin activation, is particularly well suited to modulate prolonged changes in cell adhesiveness/motility during cell differentiation and cancer.