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, Peroxovanadium compounds activate the IRK by inhibiting IR-associated phosphotyrosine phosphatase(s). Following the administration of the phosphotyrosine phosphatase inhibitor bisperoxo(1,10-phenanthroline)oxovanadate (V) anion (bpV(phen)) activation of the hepatic IRK in ENs preceded that in PM by 5 min. When colchicine treatment preceded bpV(phen) administration IRK activation in ENs was unaffected but was totally abrogated in PM. Insulin receptor substrate-1 tyrosine phosphorylation followed the kinetics of IRK activation in ENs not PM and a hypoglycemic response similar to that achieved with a pharmacological dose of insulin ensued. These studies demonstrate that ENs constitute a site for IR-mediated signal transduction.