McElroy Brian, Powell James C, McCarthy Justin V
Signal Transduction Laboratory, Biochemistry Department, National University of Ireland, Cork, Ireland.
Biochem Biophys Res Commun. 2007 Jul 13;358(4):1136-41. doi: 10.1016/j.bbrc.2007.05.062. Epub 2007 May 21.
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.
几种1型膜蛋白会经历受调控的膜内蛋白水解，从而产生具有生物活性的蛋白片段。早老素依赖性γ-分泌酶活性是这一过程的核心，淀粉样前体蛋白（APP）、Notch和ErbB4作为其底物。在此我们表明，胰岛素样生长因子1受体（IGF-IR）会经历受调控的膜内蛋白水解。一种依赖金属蛋白酶的胞外域脱落事件会产生一个约52 kDa的IGF-IR羧基末端结构域（CTD）。IGF-IR-CTD继而成为γ-分泌酶切割的底物，释放出一个约50 kDa的细胞内结构域（ICD），该结构域可被一种特异性γ-分泌酶抑制剂抑制。这项研究表明，IGF-IR是γ-分泌酶的底物，可能介导一种独立于其作为受体酪氨酸激酶作用的功能。
