Grochowski Christopher M, Loomes Kathleen M, Spinner Nancy B
Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Pediatric Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Gene. 2016 Jan 15;576(1 Pt 3):381-4. doi: 10.1016/j.gene.2015.10.065. Epub 2015 Nov 6.
Jagged1 (JAG1) is one of the 5 cell surface ligands that functions primarily in the highly conserved Notch signaling pathway. Notch signaling plays a critical role in cellular fate determination and is active throughout development and across many organ systems. The classic JAG1-NOTCH interaction leads to a cascade of proteolytic cleavages resulting in the NOTCH intracellular domain being transported into the nucleus where it functions to activate downstream transcription of target genes. JAG1 mutations have been associated with several disorders including the multi-system dominant disorder Alagille syndrome, and some cases of tetralogy of Fallot (although these may represent variable expressivity of Alagille syndrome). In addition, variations in JAG1 have been found to be associated with multiple types of cancer including breast cancer and adrenocortical carcinoma. Alagille syndrome, which primarily affects the liver, heart, skeleton, eye, face, kidney and vasculature is caused by loss of function mutations in JAG1, demonstrating that haploinsufficiency for JAG1 is disease causing, at least in these tissues. Expression and conditional gene knockout studies of JAG1 (Jag1) have correlated with tissue-specific disease phenotypes and have provided insight into both disease pathogenesis and human development.
锯齿状蛋白1（JAG1）是5种细胞表面配体之一，主要在高度保守的Notch信号通路中发挥作用。Notch信号在细胞命运决定中起关键作用，在整个发育过程以及许多器官系统中均有活性。经典的JAG1-Notch相互作用会引发一系列蛋白水解切割，导致Notch细胞内结构域被转运到细胞核中，在那里它发挥作用激活靶基因的下游转录。JAG1突变与多种疾病相关，包括多系统显性疾病阿拉吉列综合征，以及一些法洛四联症病例（尽管这些可能代表阿拉吉列综合征的可变表达）。此外，已发现JAG1的变异与多种类型的癌症相关，包括乳腺癌和肾上腺皮质癌。主要影响肝脏、心脏、骨骼、眼睛、面部、肾脏和脉管系统的阿拉吉列综合征是由JAG1的功能丧失突变引起的，这表明JAG1的单倍剂量不足至少在这些组织中会导致疾病。JAG1（Jag1）的表达和条件性基因敲除研究与组织特异性疾病表型相关，并为疾病发病机制和人类发育提供了见解。
