Biemesderfer D
Section of Nephrology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut 06520, USA.
Kidney Int. 2006 May;69(10):1717-21. doi: 10.1038/sj.ki.5000298.
Regulated intramembrane proteolysis (RIP) represents an evolutionarily conserved process linking receptor function with transcriptional regulation. Best characterized by the Notch signaling pathway, RIP involves regulated ectodomain shedding followed by gamma-secretase-mediated release of the C-terminal, cytosolic domain. The C-terminus in turn translocates to the nucleus where it interacts with other proteins to regulate expression of specific genes. Recent studies in our laboratory have shown that megalin, a scavenger receptor in proximal tubule, is subjected to RIP in a manner very similar to that of Notch. We showed that megalin in subjected to protein kinase C-regulated, metalloprotease-mediated ectodomain shedding producing a membrane-associated C-terminal fragment (MCTF). The MCTF in turn forms the substrate for gamma-secretase. These data implicate megalin as a central element of a Notch-like signaling pathway linking protein reabsorption and gene regulation in proximal tubule. The likelihood that megalin processing plays an important role in the progression of proteinuric kidney disease is discussed.
调节性膜内蛋白水解（RIP）是一个将受体功能与转录调控联系起来的进化保守过程。以Notch信号通路最为典型，RIP包括调节性胞外域脱落，随后由γ-分泌酶介导释放C末端胞质结构域。C末端继而转位至细胞核，在那里它与其他蛋白质相互作用以调节特定基因的表达。我们实验室最近的研究表明，近端小管中的清道夫受体巨蛋白以与Notch非常相似的方式经历RIP。我们发现巨蛋白受到蛋白激酶C调节、金属蛋白酶介导的胞外域脱落，产生膜相关的C末端片段（MCTF）。MCTF继而成为γ-分泌酶的底物。这些数据表明巨蛋白是近端小管中连接蛋白质重吸收和基因调控的Notch样信号通路的核心元件。本文讨论了巨蛋白加工在蛋白尿性肾病进展中发挥重要作用的可能性。
