Notch Inhibition of RAS Signaling Through MAP Kinase Phosphatase LIP-1 During C. elegans Vulval Development

Abstract

During Caenorhabditis elegans vulval development, a signal from the anchor cell stimulates the RTK/RAS/MAPK (receptor tyrosine kinase/RAS/mitogen-activated protein kinase) signaling pathway in the closest vulval precursor cell P6.p to induce the primary fate. A lateral signal from P6.p then activates the Notch signaling pathway in the neighboring cells P5.p and P7.p to prevent them from adopting the primary fate and to specify the secondary fate. The MAP kinase phosphatase LIP-1 mediates this lateral inhibition of the primary fate. LIN-12/NOTCH up-regulates lip-1 transcription in P5.p and P7.p where LIP-1 inactivates the MAP kinase to inhibit primary fate specification. LIP-1 thus links the two signaling pathways to generate a pattern.

Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents

“…This suggests that the aberrant Notch-1 activation in Ras-transformed cells represents the pathological counterpart of a physiological feedback mechanism between Ras and Notch. In this model, which is consistent with published evidence (Ikeya and Hayashi, 1999;Ruiz-Hidalgo et al, 1999;Fitzgerald et al, 2000;Berset et al, 2001;Carmena et al, 2002;Shaye and Greenwald, 2002;Weijzen et al, 2002a) excessive Ras activation would trigger aberrant Notch activation, which then mediates key elements of the Ras transformed phenotype but still requires Ras to be stably tolerated by transformed cells. In human mesothelial cells transformed by the SV40 virus in the absence of Ras, an ERK-dependent transcriptional mechanism which required both large and small T oncoproteins is responsible for Notch-1 upregulation (Bocchetta et al, 2003) and in the case of HPV16 oncoproteins E6 and E7, both transcriptional and posttranscriptional mechanisms operate (Weijzen et al, 2003).…”

Signal integration during development: Insights from the Drosophila eye

“…Why is it that R7 needs two RTKs to accomplish a task that R1/R6 perform with only one? Perhaps the need for Notch pathway activation in R7 has the side effect of reducing RTK/Ras/MAPK activity, possibly by transcriptional activation of a MAPK phosphatase as seen in C. elegans (Berset et al, 2001) or else by upregulating yan expression (Rohrbaugh et al, 2002). An alternative explanation is that Notch signaling up-regulates Ttk88 as has been demonstrated in the developing PNS (Guo et al, 1996;Okabe et al, 2001;Pi et al, 2001).…”

“…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.…”

“…This function is opposed by signaling through the Notch homolog LIN-12 (Greenwald, 1998;Wang and Sternberg, 2001). LIN-12 antagonizes the LET-23 pathway by activating lip-1, which encodes a MAPK phosphatase (Berset et al, 2001) that dephosphorylates MAPK, returning it to its inactive state. This mechanism may also be at work in Drosophila, because loss of Notch function in the developing eye increases MAPK activation in PNCs (Kumar et al, 1998(Kumar et al, , 2003.…”

La signalisation RTK/RAS/ERK élargie

“…PTP-ER est ellemême phosphorylée et inactivée par ERK, décrivant ainsi une boucle de rétroaction. Par ailleurs, MKP3, une phosphatase à double spécificité (sérine/thréo-nine et tyrosine) agissant aussi sur ERK, a été mise en évidence par homologie de séquence chez la mouche et le nématode [45,46]. Une étude chez la drosophile a montré que PTP-ER et MKP3 peuvent agir indépen-damment l'une de l'autre, ou de manière concertée selon le contexte cellulaire [47].…”