Regulation of insulin receptor kinase activity by endosomal processes: possible areas for therapeutic intervention

The insulin receptor kinase (IRK) is activated following insulin binding and is rapidly internalized into endosomes (ENs) from which signaling occurs. Four endosomal processes limit the intensity and duration of intracellular signal transduction: (i) insulin degradation by an endosomal acidic insulinase, cathepsin D, which removes the ligand leading to receptor deactivation; (ii) IRK dephosphorylation by an associated protein tyrosine phosphatase abrogates its activated state; (iii) acidification of ENs changes IRK conformation reducing its affinity for ligand and inactivating its kinase; and (iv) trafficking within ENs can sequester activated IRK from signal transduction elements. Each process presents an opportunity for new potential therapeutic approaches.