Regulation of insulin receptor kinase activity by endosomal processes: possible areas for therapeutic intervention
Posner, B.I.
Current Opinion in Investigational Drugs 4(4): 430-434
2003
ISSN/ISBN: 1472-4472 PMID: 12808882 Document Number: 554513
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.