Distinct roles of EGF repeats for the Notch signaling system.
Notch is a single-pass transmembrane receptor that mediates cell fate choice in various species and developmental contexts. The Notch signal is transduced by its intracellular domain, which acts as a transcriptional activator, and is released from the plasma membrane by proteolytic cleavages. This process is initiated by intercellular association of the epidermal growth factor (EGF) repeats between Notch and the DSL (Delta, Serrate, Lag-2) ligands but the detailed mechanism is yet to be clarified. Here we demonstrate that Notch1 can form homodimers, which is achieved by its EGF motifs. The Notch1 dimer formation increased in response to ligand presentation and HES1 promoter was stimulated, implying that receptor homodimerization is an important initial step in Notch signal transduction. EGF motifs also serve as a protection against proteases, including TNF-alpha converting enzyme, which prevents Notch1 from ligand-independent activation. Multiple functions of the Notch EGF motifs, such as the prevention of constitutive activation, reciprocal interaction with the ligands and lateral interaction for homodimerization, appear to constitute crucial elements of the Notch signaling system.
Sakamoto
Kei
K
Molecular Pathology, Graduate School of Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan. s-kei.mpa@tmd.ac.jp
Chao
Wang Sheng
WS
Katsube
Ken-ichi
K
Yamaguchi
Akira
A
D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D019281:Dimerization; D004330:Drosophila; D029721:Drosophila Proteins; D004815:Epidermal Growth Factor / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic; D051880:Receptors, Notch; D012091:Repetitive Sequences, Nucleic Acid; D015398:Signal Transduction
D029721:Drosophila Proteins; D008024:Ligands; D008565:Membrane Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; D004815:Epidermal Growth Factor