Lesa, Giovanni M. and Sternberg, Paul W. (1997) Positive and negative tissue-specific signaling by a nematode epidermal growth factor receptor. Molecular Biology of the Cell, 8 (5). pp. 779-793. ISSN 1059-1524 http://resolver.caltech.edu/CaltechAUTHORS:LESmbc97
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The major determinants of receptor tissue tyrosine kinase (RTK) signaling specificity have been proposed to be Src homology 2 (SH2) binding sites, phosphotyrosine-containing oligopeptides in the cytoplasmic domain of the receptor. The Caenorhabditis elegans epidermal growth factor receptor homologue LET-23 has multiple functions during development and has eight potential SH2-binding sites in a region carboxyl terminal to its kinase domain. By analyzing transgenic nematodes for three distinct LET-23 functions, we show that six of eight potential sites function in vivo and that they are required for most, but not all, of LET-23 activity. A single site is necessary and sufficient to promote wild-type fertility. Three other sites activate the RAS pathway and are involved only in viability and vulval differentiation. A fifth site is promiscuous and can mediate all three LET-23 functions. An additional site mediates tissue-specific negative regulation. Putative SH2 binding sites are thus key effectors of both cell-specific and negative regulation in an intact organism. We suggest two distinct mechanisms for tissue-specific RTK-mediated signaling. A positive mechanism would promote RTK function through effectors present only in certain cell types. A negative mechanism would inhibit RTK function through tissue-specific negative regulators.
|Additional Information:||Copyright © 1997 by The American Society for Cell Biology Submitted December 11, 1996; Accepted February 3, 1997 We thank Raffi Aroian whose contribution was invaluable to the completion of this work. We are also deeply indebted to Tom Clandinin for suggestions and discussions. We thank Raffi Aroian, Tom Clandinin, Marie-Anne Felix, Neil Hopper, Giovanna Lalli, and Robert Palmer for critical reading of the manuscript. This work was supported by United States National Institutes of Health grant HD23690 to P.W.S. P.W.S. is an investigator with the Howard Hughes Medical Institute. G.M.L. was a Merck Graduate Fellow.|
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|Deposited On:||17 Nov 2006|
|Last Modified:||26 Dec 2012 09:17|
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