High levels of Notch signaling down-regulate Numb and Numblike.
Inhibition of Notch signaling by Numb is critical for many cell fate decisions. In this study, we demonstrate a more complex relationship between Notch and the two vertebrate Numb homologues Numb and Numblike. Although Numb and Numblike at low levels of Notch signaling negatively regulated Notch, high levels of Notch signaling conversely led to a reduction of Numb and Numblike protein levels in cultured cells and in the developing chick central nervous system. The Notch intracellular domain but not the canonical Notch downstream proteins Hes 1 and Hey 1 caused a reduction of Numb and Numblike. The Notch-mediated reduction of Numblike required the PEST domain in the Numblike protein and was blocked by the proteasome inhibitor MG132. Collectively, these observations reveal a reciprocal negative regulation between Notch and Numb/Numblike, which may be of relevance for stabilizing asymmetric cell fate switches and for tumor development.
Chapman
Gavin
G
Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, SE-171 77 Stockholm, Sweden.
Liu
Lining
L
Sahlgren
Cecilia
C
Dahlqvist
Camilla
C
Lendahl
Urban
U
D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D032446:Myoblasts / Q000166:cytology; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch