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

Nature volume 405, pages 364–368 (2000)Cite this article

Abstract

Notch signalling controls growth, differentiation and patterning during normal animal development1,2; in humans, aberrant Notch signalling has been implicated in cancer and stroke3,4. The mechanism of Notch signalling is thought to require cleavage of the receptor in response to ligand binding5, movement of the receptor's intracellular domain to the nucleus6,7, 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 protein10 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.

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Figure 1: LAG-3 and ternary complex formation in yeast.
Figure 2: LAG-3 forms a ternary complex in vitro with GLP-1(RAM-ANK) and LAG-1.
Figure 3: lag-3 is critical for both glp-1 and lin-12 signalling.
Figure 4: LAG-3 may function as a transcriptional activator.

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Acknowledgements

We acknowledge A. Puoti for providing the plasmid form of the cDNA library; R. Sternglanz, S. M. Hollenberg and A. Grimson for yeast strains and plasmids; and A. Steinberg and L. Vanderploeg for help with the illustrations. A.G.P. is an Howard Hughes Medical Institute predoctoral fellow. J.K. is an investigator of the Howard Hughes Medical Institute.

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  1. Howard Hughes Medical Institute and Department of Biochemistry University of Wisconsin-Madison, 433 Babcock Drive, Madison, 53706, Wisconsin, USA

    Andrei G. Petcherski & Judith Kimble

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  2. Judith Kimble
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Correspondence to Judith Kimble.

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Petcherski, A., Kimble, J. LAG-3 is a putative transcriptional activator in the C. elegans Notch pathway. Nature 405, 364–368 (2000). https://doi.org/10.1038/35012645

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