SELECTIVE ACTIVATION OF THE RAT HEPATIC ENDOSOMAL INSULIN-RECEPTOR KINASE - ROLE FOR THE ENDOSOME IN INSULIN SIGNALING

Insulin administration activates the insulin receptor kinase (IRK) in both plasma membrane (PM) and endosomes (ENs) raising the possibility of transmembrane signaling occurring in the endosomal compartment, Per oxovanadium compounds activate the IRK by inhibiting IR-associated pho sphotyrosine phosphatase(s). Following the administration of the phosp hotyrosine phosphatase inhibitor bisperoxo(1,10-phenanthroline)oxovana date (V) anion (bpV(phen)) activation of the hepatic IRK in ENs preced ed that in PM by 5 min. When colchicine treatment preceded bpV(phen) a dministration IRK activation in ENs was unaffected but was totally abr ogated in PM. Insulin receptor substrate-1 tyrosine phosphorylation fo llowed the kinetics of IRK activation in ENs not PM and a hypoglycemic response similar to that achieved with a pharmacological dose of insu lin ensued. These studies demonstrate that ENs constitute a site for I R-mediated signal transduction.