The insulin-like growth factor 1 (IGF-1) receptor is a substrate for gamma-secretase-mediated intramembrane proteolysis.
Several type-1 membrane proteins undergo regulated intramembrane proteolysis resulting in the generation of biologically active protein fragments. Presenilin-dependant gamma-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 approximately 52 kDa IGF-IR-carboxyl terminal domain (CTD). The IGF-IR-CTD is consequentially a substrate for gamma-secretase cleavage, liberating a approximately 50 kDa intracellular domain (ICD) that can be inhibited by a specific gamma-secretase inhibitor. This study suggests that the IGF-IR is a substrate for gamma-secretase and may mediate a function independent of its role as a receptor tyrosine kinase.
McElroy
Brian
B
Signal Transduction Laboratory, Biochemistry Department, National University of Ireland, Cork, Ireland.
Powell
James C
JC
McCarthy
Justin V
JV
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010447:Peptide Hydrolases / Q000378:metabolism*; D053763:Presenilins / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
D053763:Presenilins; D017526:Receptor, IGF Type 1; D053829:Amyloid Precursor Protein Secretases; D010447:Peptide Hydrolases