INTERACTION OF CLASS-I HUMAN-LEUKOCYTE ANTIGEN (HLA-I) MOLECULES WITHINSULIN-RECEPTORS AND ITS EFFECT ON THE INSULIN-SIGNALING CASCADE

Insulin receptor (LR) and class I major histocompatibility complex mol ecules associate with one another in cell membranes, but the functiona l consequences of this association are not defined. We found that IR a nd human class I molecules (HLA-I) associate in liposome membranes and that the affinity of IR for insulin and its tyrosine kinase activity increase as the HLA:IR ratio increases over the range 1:1 to 20:1. The same relationship between HLA:IR and IR function was found in a serie s of B-LCL cell lines. The association of HLA-I and IR depends upon th e presence of free HLA heavy chains. All of the effects noted were red uced or abrogated if liposomes or cells were incubated with excess HLA -I light chain, beta 2-microglobulin. Increasing HLA:IR also enhanced phosphorylation of insulin receptor substrate-1 and the activation of phosphoinositide 3-kinase. HLA-I molecules themselves were phosphoryla ted on tyrosine and associated with phosphoinositide 3-kinase when B-L CL were stimulated with insulin.