Azimi Mina, Brown Nadean L
Department of Cell Biology & Human Anatomy, University of California, 1 Shields Avenue, Davis, CA 95616, USA.
Department of Cell Biology & Human Anatomy, University of California, 1 Shields Avenue, Davis, CA 95616, USA
Biol Open. 2019 Mar 26;8(3):bio041095. doi: 10.1242/bio.041095.
Notch signaling regulates a multitude of cellular processes. During ocular lens development this pathway is required for lens progenitor growth, differentiation and maintenance of the transition zone. After ligand-receptor binding, the receptor proteins are processed, first by ADAM proteases, then by γ-secretase cleavage. This results in the release of a Notch intracellular domain (N-ICD), which is recruited into a nuclear transcription factor complex that activates Notch target genes. Previous studies showed that the Delta-like and Jagged ligand proteins can also be cleaved by the γ-secretase complex, but it remains unknown whether such processing occurs during vertebrate development. Here we show that mouse and human lens progenitor cells endogenously express multiple Jagged1 protein isoforms, including a Jagged1 intracellular domain. We also found that pharmacologic blockage of γ-secretase activity resulted in an accumulation of Jagged1 polypeptide intermediates. Finally, overexpression of an epitope-tagged Jagged1 intracellular domain displayed nuclear localization and induced the upregulation of endogenous mRNA expression. These findings support the idea that along with its classical role as a Notch pathway ligand, Jagged1 is regulated post-translationally, to produce multiple active protein isoforms.
Notch信号通路调控众多细胞过程。在眼晶状体发育过程中，该信号通路对于晶状体祖细胞的生长、分化以及过渡区的维持是必需的。配体与受体结合后，受体蛋白首先由ADAM蛋白酶进行加工处理，然后通过γ-分泌酶切割。这导致Notch胞内结构域（N-ICD）的释放，其被招募到一个核转录因子复合物中，该复合物激活Notch靶基因。先前的研究表明，Delta样和锯齿状配体蛋白也可被γ-分泌酶复合物切割，但在脊椎动物发育过程中这种加工是否发生仍不清楚。在此我们表明，小鼠和人类晶状体祖细胞内源性表达多种锯齿状蛋白1（Jagged1）异构体，包括Jagged1胞内结构域。我们还发现，γ-分泌酶活性的药理学阻断导致Jagged1多肽中间体的积累。最后，表位标记的Jagged1胞内结构域的过表达显示出核定位并诱导内源性mRNA表达上调。这些发现支持这样一种观点，即除了作为Notch信号通路配体的经典作用外，Jagged1在翻译后受到调控，以产生多种活性蛋白异构体。
