| The Notch signal transduction pathway is critical for cell-cell communications during animal development. Signal transduction by the Notch pathway is a multi-step process: in response to ligand binding, the intracellular part of the Notch receptor is cleaved and moves to the nucleus, where it binds CSL factor, a DNA binding protein. This sequence of events culminates in transcriptional activation of target promoters. How Notch intracellular domain activates transcription is unknown. LAG-3, a novel protein from C. elegans, forms a ternary complex with C. elegans CSL factor, LAG-1, and the intracellular domain of Notch. lag-3 is critical for Notch signaling by several criteria. First, the mutations in the ankyrin domain of the receptor that disrupt receptor function in vivo also disrupt the ternary complex. Second, removal of lag-3 activity in worms using RNA interference results in phenotypes characteristic of loss-of-function phenotypes for Notch receptors. Third, removal of lag-3 activity using RNA interference suppresses phenotypes of gain-of-function alleles of Notch receptors. LAG-3 is a glutamine-rich protein that localizes to the nucleus in worms, and is a strong transcriptional activator in yeast. I propose that, in C. elegans, LAG-3 functions as a transcriptional co-activator in the ternary complex with the intracellular domain of Notch and the CSL factor.; In addition, I demonstrate that Mastermind proteins from fly and mouse form ternary complexes with the corresponding Notch receptors and CSL factors. In flies Mastermind is a nuclear protein rich in glutamines and prolines critical for Notch signaling. I propose that Mastermind proteins in fly and mouse can serve functions analogous to that of LAG-3 in C. elegans as transcriptional co-activators for Notch and as part of the corresponding ternary complexes. |
