Thus, the early studies unveiling the physiological relevance of the cis-association between open HLA-I conformers and the IR:insulin complex, namely the regulation of the activity of intracellular kinases PI3K, ERK, and AKT, are inextricably linked to recent studies that have deepened our understanding of the physiological importance of modulating intracellular metabolic pathways in cancer biology and CNS function [206]. Here, INS is linked to cancer.