The insulin-like growth factor 1 (IGF-1) receptor is a substrate for γ-secretase-mediated intramembrane proteolysis

Several type-1 membrane proteins undergo regulated intramembrane proteolysis resulting in the generation of biologically active protein fragments. Presenilin-dependant γ-secretase activity is central to this event and includes amyloid precursor protein (APP), Notch and ErbB4 as substrates. Here we show that the insulin-like growth factor 1 receptor (IGF-IR) undergoes regulated intramembrane proteolysis. A metalloprotease-dependant ectodomain-shedding event generates a ∼52 kDa IGF-IR-carboxyl terminal domain (CTD). The IGF-IR-CTD is consequentially a substrate for γ-secretase cleavage, liberating a ∼50 kDa intracellular domain (ICD) that can be inhibited by a specific γ-secretase inhibitor. This study suggests that the IGF-IR is a substrate for γ-secretase and may mediate a function independent of its role as a receptor tyrosine kinase.