Cellular activation of latent transforming growth factor β requires binding to the cation-independent mannose 6-phosphate/insulin-like growth factor type II receptor

The activation of latent transforming growth factor β (LTGF-β) normally seen in cocultures of bovine aortic endothelial and bovine smooth muscle cells can be inhibited by coculturing the cells with either mannose 6-phosphate (Man-6-P) or antibodies directed against the cation-independent Man-6-P/insulin-like growth factor type II receptor (anti-Man-6-PR). This result was established by measuring the ability of coculture conditioned medium (formed with or without Man-6-P or anti-Man-6-PR) to suppress bovine aortic endothelial cell migration and protease production, activities previously shown to be related to transforming growth factor β activity. The inhibition by Man-6-P is dose dependent, with maximal inhibition seen at 100 μM, and is specific because mannose 1-phosphate and glucose 6-phosphate do not interfere with activation of LTGF-β. The inhibitory effect of anti-Man-6-PR is also specific and dose dependent; maximal inhibition of activation occurs at 400 μg/ml. Control experiments indicate that Man-6-P and anti-Man-6-PR do not interfere with the basal level of migration of bovine aortic endothelial cells, the migration observed when exogenous transforming growth factor β is added, the activation of transforming growth factor β by plasmin or transient acidification, and the release of LTGF-β. Thus, binding to the cation-independent Man-6-P/insulin-like growth factor type II receptor appears to be a requirement for activation of LTGF-β.