Receptors of the LIN-12/Notch family are found throughout the animal kingdom and are activated by binding ligands of the Delta/Serrate/LAG-2 family. In order to understand the consequences of receptor activation that result in cell fate decisions, modifiers and regulators of the pathway must be identified and characterized. One way to influence the outcome of ligand-receptor interactions is to regulate the stability of the ligand, the receptor or downstream components of the pathway. We have identified and characterized
sel-10, a potent modifier of the
lin-12 pathway that appears to act at the level of protein turnover. Mutations in
sel-10 were identified in a screen for suppressors of phenotypes associated with reduced
lin-12 activity (Sundaram and Greenwald, 1993). Hypomorphic alleles of
sel-10 suppress defects associated with reduced
lin-12 activity and dramatically enhance defects associated with constitutively activated
lin-12 alleles, including defects caused by expression of the
lin-12 intracellular domain. In addition,
sel-10 mutants display low penetrance phenotypes associated with increased
lin-12 activity. Therefore, reduction of
sel-10 elevates
lin-12 activity, implicating
sel-10(+) in negative regulation of
lin-12 signalling. Using an anti-suppression assay, we cloned
sel-10 and found that it encodes a member of the CDC4 subfamily of WD40 repeat containing proteins. In yeast, CDC4 is involved in targeting cell-cycle control proteins for degradation via ubiquitination. We have obtained preliminary biochemical evidence that SEL-10 can reduce the steady-state level of LIN-12/Notch proteins, and we are currently testing the hypothesis that SEL-10 influences
lin-12-mediated signalling by reducing the steady-state level of the activated receptor.