Functional Analysis of Human Eph Receptor Homologs Using C. elegans as a Model

Abstract

The Eph receptor tyrosine kinases are a highly conserved family of proteins involved in a variety of developmental processes. As well, the Eph receptors appear to play a pivotal role in the development and progression of some cancers. The nematode C. elegans has emerged as a strong developmental model, for the study of human Eph receptors. Recent research in this model, has suggested an antagonistic relationship between VAB-1, the single C. elegans Eph receptor and DAF-18, the homolog of the human tumor suppressor PTEN. This work in C. elegans has led to the hypothesis that the human Eph receptors and PTEN may function in a similar way. To provide evidence to support this hypothesis I showed that human EPHA2 and PTEN could physically interact in vitro. Furthermore, my research shows that the human Eph receptors appear to function like the C. elegans Eph receptor (VAB-1) in the neurons of the worm. Finally, I provided evidence to show that EphA3 K761N, a common mutation found in human lung cancers, behaves like a gain-of-function mutation in C. elegans. Expressing EphA3 K761N or the analogous mutation in VAB-1, K859N, results in overactive receptor tyrosine kinase activity leading to abnormal axon guidance in C. elegans. These results have furthered our understanding of the evolutionary conservation between the human Eph receptors and VAB-1, and show the promise of using this model to discover novel components of the human Eph receptor signaling pathway.