Pfister Sabine, Przemeck Gerhard K H, Gerber Josef-Karl, Beckers Johannes, Adamski Jerzy, Hrabé de Angelis Martin
GSF-National Research Center for Environment and Health, Institute of Experimental Genetics, Ingolstaedter Landstr 1, D-85764 Neuherberg, Germany.
J Mol Biol. 2003 Oct 17;333(2):229-35. doi: 10.1016/j.jmb.2003.08.043.
The evolutionarily conserved Notch signal transduction pathway regulates cell fate and cellular differentiation in various tissues and has essential functions in embryonic patterning and tumorigenesis. Cell-cell signaling by the Notch pathway is mediated by the interaction of the transmembrane receptor Notch with its ligands Delta or Jagged presented on adjacent cells. Whereas signal transduction to Notch expressing cells has been described, it is unclear whether Delta-dependent signaling may exist within the Delta-expressing cell. Here, we report on the identification of Acvrinp1, a MAGUK family member, interacting with the intracellular domain of Delta1 (Dll1). We confirmed the interaction between Dll1 and Acvrinp1 by pull-down experiments in vitro and in a mammalian two-hybrid system in vivo. We delimited the fourth PDZ domain of Acvrinp1 and the PDZ-binding domain of Dll1 as major interacting domains. In situ expression analyses in mouse embryos revealed that Dll1 and Acvrinp1 show partly overlapping but distinct expression patterns, for example, in the central nervous system and the vibrissae buds. Further, we found that expression of Acvrinp1 is altered in Dll1 loss-of-function mouse embryos.
进化上保守的Notch信号转导通路调节多种组织中的细胞命运和细胞分化，在胚胎模式形成和肿瘤发生中具有重要作用。Notch通路的细胞间信号传导是由跨膜受体Notch与其相邻细胞上呈现的配体Delta或Jagged相互作用介导的。虽然已经描述了向表达Notch的细胞的信号转导，但尚不清楚在表达Delta的细胞内是否可能存在Delta依赖性信号传导。在这里，我们报告了对Acvrinp1的鉴定，它是一种MAGUK家族成员，与Delta1（Dll1）的细胞内结构域相互作用。我们通过体外下拉实验和体内哺乳动物双杂交系统证实了Dll1和Acvrinp1之间的相互作用。我们将Acvrinp1的第四个PDZ结构域和Dll1的PDZ结合结构域确定为主要相互作用结构域。在小鼠胚胎中的原位表达分析表明，Dll1和Acvrinp1显示出部分重叠但不同的表达模式，例如，在中枢神经系统和触须芽中。此外，我们发现Acvrinp1的表达在Dll1功能丧失的小鼠胚胎中发生了改变。
