LAG-3 is a putative transcriptional activator in the C-elegans Notch pathway

Notch signalling controls growth, differentiation and patterning during normal animal development(1,2); in humans, aberrant Notch signalling has been implicated in cancer and stroke(3,4). The mechanism of Notch signalling is thought to require cleavage of the receptor in response to ligand binding(5), movement of the receptor's intracellular domain to the nucleus(6,7), and binding of that intracellular domain to a CSL (for CBF1, Suppressor of Hairless, LAG-1)(8,9) protein. Here we identify LAG-3, a glutamine-rich protein that forms a ternary complex together with the LAG-1 DNA-binding protein(10) and the receptor's intracellular domain. Receptors with mutant ankyrin repeats that abrogate signal transduction are incapable of complex formation both in yeast and in vitro. Using RNA interference, we find that LAG-3 activity is crucial in Caenorhabditis elegans for both GLP-1 and LIN-12 signalling. LAG-3 is a potent transcriptional activator in yeast, and a Myc-tagged LAG-3 is predominantly nuclear in C. elegans. We propose that GLP-1 and LIN-12 promote signalling by recruiting LAG-3 to target promoters, where it functions as a transcriptional activator.