title: Generation of intracellular domain of insulin receptor tyrosine kinase by gamma-secretase.
abstract: The proteolytic cleavage of a precursor protein into alpha- and beta-subunits by furin is required to form functional insulin receptor (IR). In this study, we examined if IR undergoes the additional presenilin (PS)/gamma-secretase-dependent processing. In cells treated with gamma-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/gamma-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/gamma-secretase-dependent processing. We also show that the autophosphorylation levels of the IR beta-subunit upon insulin stimulation were decreased by the inactivation of PS/gamma-secretase, raising the possibility that the PS/gamma-secretase proteolysis of IR may play a modulatory role in insulin signaling.
authors.affiliation: Department of Molecular Neuroscience, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951-8585, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kasuga
authors.forename: H
authors.initials: H
authors.lastname: Kaneko
authors.forename: M
authors.initials: M
authors.lastname: Nishizawa
authors.forename: O
authors.initials: O
authors.lastname: Onodera
authors.forename: T
authors.initials: T
authors.lastname: Ikeuchi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011972:Receptor, Insulin; D053829:Amyloid Precursor Protein Secretases