ANNEXIN-II IS A NOVEL PLAYER IN INSULIN SIGNAL-TRANSDUCTION - POSSIBLE ASSOCIATION BETWEEN ANNEXIN-II PHOSPHORYLATION AND INSULIN-RECEPTOR INTERNALIZATION

Annexin II is a Ca2+-, phospholipid-, and actin- binding protein that was implicated in the regulation of vesicular traffic and endosome fus ion. It is a known substrate for protein kinases including the platele t-derived growth factor receptor, src protein-tyrosine kinase, and pro tein kinase C. In the present study we investigated the possible invol vement of annexin II in insulin signal transduction. Phosphorylation o f annexin II in response to insulin treatment of intact Chinese hamste r ovary (CHO)-T cells was detected by 5 min and reached maximal levels after a 2-3-h incubation with the hormone, However, unlike other rece ptor substrates, annexin II failed to undergo insulin induced Tyr phos phorylation under conditions where receptor internalization was inhibi ted. This was evident in CHO cells, overexpressing the insulin recepto r, in which internalization was inhibited either by tyrosine kinase in hibitors or by lowering the temperature to 4 degrees C, and in CHO cel ls overexpressing various insulin receptor mutants in which normal int ernalization was impaired. Hence, Tyr phosphorylation of annexin II co uld be part of the internalization and sorting mechanism of the insuli n receptor.