Signaling by LET-23, a Caenorhabditis elegans Epidermal Growth Factor Receptor Homolog

Citation

Lesa, Giovanni M. (1998) Signaling by LET-23, a Caenorhabditis elegans Epidermal Growth Factor Receptor Homolog. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/ywxy-2h20. https://resolver.caltech.edu/CaltechTHESIS:07292025-220045090

Abstract

The Caenorhabditis elegans gene let-23 encodes a tyrosine kinase of the Epidermal Growth Factor Receptor (EGFR) family. Ligand-independent activation of EGFR tyrosine kinases is involved in many types of cancer. A ligand-independent activating mutation of let-23, sa62, has been characterized. sa62 maps to the extracellular domain of the LET-23 protein and results in excessive proliferation of the cells which forms the hermaphrodite vulva. Analysis of sa62 has suggested that the region to which it maps is important for transmembrane activation of LET-23 signaling.

let-23 mediates multiple functions in C. elegans including viability, vulval differentiation, and fertility. Analysis of tissue specific and loss-of-function mutations of let-23 suggested that the C-terminus of LET-23 can be divided into at least three domains, each mediating a subset of let-23 functions. The EGFR family of tyrosine kinases contain potential C-terminal phosphotyrosines whose role is still unclear. Using in vitro mutagenesis and transgenic technology, this thesis shows that in vivo the LET-23 C-terminal tyrosines are required for wild-type activity and that they are differently used to mediate cell specific, positive, and negative regulation. One tyrosine is necessary and sufficient for wild-type fertility. Three other tyrosines are involved in viability and vulval differentiation. Another tyrosine appears to mediate tissue specific negative regulation. Two mechanisms are proposed for receptor tyrosine kinase signaling: a positive mechanism, which promote, and a negative mechanism, which inhibits receptor tyrosine kinase activity. It is also shown that LET-23 activates at least two pathways: the Ras pathway to mediate viability and vulval differentiation, and another pathway to mediate fertility. A genetic screen to identify genes acting positively in the let-23-mediated fertility pathway is described. In addition, the initial characterization of a gene acting in this pathway is reported.

Thesis Files