Positive and negative tissue-specific signaling by a nematode epidermal growth factor receptor.
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.
Lesa
G M
GM
Howard Hughes Medical Institute, California Institute of Technology, Pasadena, USA.
Sternberg
P W
PW
D000818:Animals; D030801:Animals, Genetically Modified; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005298:Fertility; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014844:Vulva; D018909:src Homology Domains
D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; C085751:Sem-5 protein, C elegans; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C085873:let-23 protein, C elegans