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  • Original Paper
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Extracellular domain determinants of LET-23 (EGF) receptor tyrosine kinase activity in Caenorhabditis elegans

Oncogene volume 22, pages 5471–5480 (2003)Cite this article

Abstract

Negative regulation of ErbB/EGFR signalling pathways is important for normal development and the prevention of cancer. In a genetic screen to uncover mechanisms that negatively regulate ErbB signalling in Caenorhabditis elegans, we isolated a second-site mutation (sy621) that promotes the activity of a gain-of-function allele (sa62gf) of the let-23 (EGF) receptor tyrosine kinase. We show that activation by the sa62 mutation (C359Y) likely results from a break in the conserved disulphide-bonded eighth module at the junction of CR1 and L2. The sy621 mutation causes a G270E change in the third disulphide-bonded module of CR1, and causes no phenotype on its own, but cooperates with the sa62 mutation to promote receptor activity. Although both sa62 single- and double-mutant receptors can function in the absence of ligand, they can be further activated by ligand. Our results support the current model for ligand-induced dimerization based on the recent crystal structures of HER3 and the EGFR, and provide more evidence for the generation of distinctly activated ErbB family members through mutation.

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Acknowledgements

We thank C Ward, G Schindelman, C Van Buskirk, D Chan, A Petcherski, BP Gupta, and the anonymous reviewers for comments and discussions. Some nematode strains were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources. This research was supported by the Howard Hughes Medical Institute of which PWS is an investigator. NM was supported by postdoctoral fellowships from the Leukemia and Lymphoma Society, and the California Breast Cancer Research Program.

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  1. Howard Hughes Medical Institute and Division of Biology, California Institute of Technology, Pasadena, 91125, CA, USA

    Nadeem Moghal & Paul W Sternberg

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  1. Nadeem Moghal
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  2. Paul W Sternberg
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Correspondence to Nadeem Moghal.

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Moghal, N., Sternberg, P. Extracellular domain determinants of LET-23 (EGF) receptor tyrosine kinase activity in Caenorhabditis elegans. Oncogene 22, 5471–5480 (2003). https://doi.org/10.1038/sj.onc.1206648

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