Intracellular cell-autonomous association of Notch and its ligands: a novel mechanism of Notch signal modification.
Notch (N) and its ligands, Delta (Dl) and Serrate (Ser), are membrane-spanning proteins with EGF repeats. They play an essential role in mediating proliferation and segregated differentiation of stem cells. One of the prominent features of N signal system is that its ligands are anchored to the plasma membrane, which allows the ligand/receptor association only between the neighboring cells. Various lines of evidences have verified this intercellular signal transmission, but there also have been implications that expression of Dl or Ser interferes cell-autonomously with the ability of the cell to receive N signal, implying that N and its ligands may interact in the same cell. Here, we demonstrate that N, Dl, and Ser cell-autonomously form homomeric or heteromeric complexes. The cell-autonomous heteromeric complexes are not present on the cell surface, implying that the association occurs in the endoreticulum or Golgi apparatus. Expression of Dl or Ser cell-autonomously reduces the N-mediated HES-5 promoter activity, indicating that the cell-autonomous association alters the N signal receptivity. Intracellular deletion of Dl shows elevated activity of this dominant-negative effect. In vivo overexpression study suggests that the cell-autonomous function of Dl and Ser is independent of the ligand specificity and may be modulated by Fringe (Fg), which inhibits the formation of the cell-autonomous Dl/N or Ser/N complex.
Sakamoto
Kei
K
Department of Oral Restitution, Graduate School, Bunkyo-ku, Tokyo 113-8549, Japan.
Ohara
Osamu
O
Takagi
Minoru
M
Takeda
Shin'ichi
S
Katsube
Ken-ichi
K
D020816:Amino Acid Motifs; D000818:Animals; D030161:Avian Proteins; D019556:COS Cells; D002135:Calcium-Binding Proteins; D002450:Cell Communication; D002460:Cell Line; D019070:Cell Lineage / Q000502:physiology; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D019281:Dimerization; D016695:Glycosyltransferases / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney; D008024:Ligands; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins / Q000502:physiology; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D014162:Transfection
D030161:Avian Proteins; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D046911:Macromolecular Substances; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D000072099:Serrate-Jagged Proteins; C064045:delta protein; D016695:Glycosyltransferases; C498394:LFNG protein, Gallus gallus; C498393:LFNG protein, human