Endocytosis-mediated downregulation of LIN-12/Notch upon Ras activation in Caenorhabditis elegans

Abstract

The coordination of signals from different pathways is important for cell fate specification during animal development. Here, we define a novel mode of crosstalk between the epidermal growth factor receptor/Ras/mitogen-activated protein kinase cascade and the LIN-12/Notch pathway during Caenorhabditis elegans vulval development. Six vulval precursor cells (VPCs) are initially equivalent but adopt different fates as a result of an inductive signal mediated by the Ras pathway and a lateral signal mediated by the LIN-12/Notch pathway. One consequence of activating Ras is a reduction of LIN-12 protein in P6.p (ref. 2), the VPC believed to be the source of the lateral signal. Here we identify a 'downregulation targeting signal' (DTS) in the LIN-12 intracellular domain, which encompasses a di-leucine-containing endocytic sorting motif. The DTS seems to be required for internalization of LIN-12, and on Ras activation it might mediate altered endocytic routing of LIN-12, leading to downregulation. We also show that if LIN-12 is stabilized in P6.p, lateral signalling is compromised, indicating that LIN-12 downregulation is important in the appropriate specification of cell fates in vivo.

Signal integration during development: Insights from the Drosophila eye

“…Antagonism between the Notch and RTK pathways has been observed in many different developmental contexts in Drosophila (de Celis and Bray, 1997; Price et al, 1997;zur Lage and Jarman, 1999;Culi et al, 2001) and other organisms (Berset et al, 2001;Shaye and Greenwald, 2002). While EGFR and Notch function predominantly an-tagonistically, it is important to note that in certain contexts, the two pathways also appear to synergize (Price et al, 1997;Carmena et al, 2002), further emphasizing the importance of the spatial and temporal context on developmental outcome.…”

PKCζ regulates Notch receptor routing and activity in a Notch signaling-dependent manner

“…It is well known that Notch receptors can be internalized, but the underlying mechanisms and effects of receptor internalization on Notch signaling activity are poorly understood [3]. There are several reports advocating that endocytosis promotes Notch activation [4][5][6][7], while other studies suggest that intracellular trafficking exerts a negative effect [8][9][10][11][12]. Similarly, there are conflicting views on where S3 processing occurs.…”

Conditional Deletion of Notch1 and Notch2 Genes in Excitatory Neurons of Postnatal Forebrain Does Not Cause Neurodegeneration or Reduction of Notch mRNAs and Proteins

“…The reduction of Notch1 and Notch2 proteins after Cre transduction is more rapid than that of PS1 protein in cortical cultures derived from floxed PS1 neonates, in which PS1 protein is completely eliminated by DIV7 (49). This difference could be due to the easier accessibility of Cre recombinase to the Notch loci (66) or shorter half-life of Notch mRNAs and proteins (67)(68)(69)(70).…”