Glomerular matrix accumulation is the hallmark of diabetic nephropathy. The metalloprotease ADAM17 mediates high glucose (HG)-induced matrix production by kidney mesangial cells through release of ligands for the epidermal growth factor receptor. Here we study the mechanism by which HG activates ADAM17. We find that the C-terminus is essential for ADAM17 activation and the profibrotic response to HG. In the C-terminus, Src-mediated Y702 phosphorylation and PI3K/MEK/Erk-mediated T735 phosphorylation are critical to ADAM17 activation, but play divergent roles in ADAM17 trafficking in response to HG. While T735 phosphorylation is required for the HG-induced increase in cell surface mature ADAM17, Y702 phosphorylation is dispensable. Src, however, enables trafficking independently of its phosphorylation of ADAM17. The nonreceptor tyrosine kinase FAK is a central mediator of these processes. These data not only support a critical role for the C-terminus in ADAM17 activation and downstream profibrotic responses to HG, but also highlight FAK as a potential alternate therapeutic target for diabetic nephropathy.