Generation of intracellular domain of insulin receptor tyrosine kinase by γ-secretase

The proteolytic cleavage of a precursor protein into α- and β-subunits by furin is required to form functional insulin receptor (IR). In this study, we examined if IR undergoes the additional presenilin (PS)/γ-secretase-dependent processing. In cells treated with γ-secretase inhibitors or expressing the dominant-negative PS1 variant led to the accumulation of an endogenous IR C-terminal fragment. In the presence of proteasome inhibitors, we detected a PS/γ-secretase cleavage product of the IR, termed the IR intracellular domain (ICD). Cellular fractionation and confocal microscopy analyses showed that the IR-ICD is predominantly detected in the nucleus. These data indicate that IR is a tyrosine kinase receptor, which undergoes PS/γ-secretase-dependent processing. We also show that the autophosphorylation levels of the IR β-subunit upon insulin stimulation were decreased by the inactivation of PS/γ-secretase, raising the possibility that the PS/γ-secretase proteolysis of IR may play a modulatory role in insulin signaling.