Numb Regulates Post-endocytic Trafficking and Degradation of Notch1

Numb regulates vesicular docking for homotypic fusion of early endosomes via membrane recruitment of Mon1b

“…Numb carries out these functions via regulating endocytic trafficking of several key molecules, such as Notch, sanpodo, cadherins and integrins [4,7,9,14,17,18,23,24,26,51,52]. Although in all these contexts Numb functions as an endocytic adaptor protein, the exact role of Numb in endocytic trafficking remains an open question.…”

“…Genetic evidence shows that Numb contributes to cell fate determination by antagonizing Notch activity in one of the two daughter cells after asymmetric cell division [2,3,22]. A recent study suggested that Numb suppresses Notch activity either by facilitating lysosomal degradation of Notch or by reducing its recycling to the plasma membrane [23]. Numb also antagonizes the Notch pathway via facilitating the endocytosis of Drosophila sanpodo, which is a membrane protein that is required for Notch activation [24].…”

Drosophila Ndfip is a novel regulator of Notch signaling

“…Also, most mammalian isoforms of Notch lack a PY motif and, therefore, depend upon known adapters to mediate the interaction with E3s, such as Itch (Su(dx) ortholog). 27,28 Recently, however, Itch-mediated turnover of Notch1 receptor in the absence of ligand has been shown to depend upon a bridging factor that is not Numb, nor Dx, nor the adapters b-arrestin 1 or 2. 28 It is possible that Ndfips serve in an adapter role in Notch regulation.…”

Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling

“…On the one hand, the protein Numb is a conserved inhibitor of the pathway that acts at this level (Cotton et al, 2013;Couturier et al, 2013Couturier et al, , 2014Reichardt and Knoblich, 2013). This factor interacts with components of the AP-2 complex and prevents endosome-to-plasma membrane recycling of Notch; in addition, Numb also promotes the lysosomal degradation of the receptor (McGill et al, 2009). In contrast, Deltex, an E3 ligase, has been shown to promote Notch signaling in a ligand-independent manner (Sakata et al, 2004;Wilkin et al, 2008;Hori et al, 2011Hori et al, , 2012Troost et al, 2012).…”

“…Notch is constantly endocytosed (McGill et al, 2009), and the signaling outcome arising from this internalized pool of Notch is carefully controlled by several factors. On the one hand, the protein Numb is a conserved inhibitor of the pathway that acts at this level (Cotton et al, 2013;Couturier et al, 2013Couturier et al, , 2014Reichardt and Knoblich, 2013).…”