INVESTIGATION OF A DOMAIN V-MEDIATED REGULATORY MECHANISM BETWEEN THE DROSOPHILA EGFR AND KEKKON1 Public
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The EGFR/ErbB receptors are receptor tyrosine kinases that play key roles in metazoan development. They have been linked to a variety of cancers due to their critical function in cellular signaling and regulation of cell division, migration, fate, and differentiation. With these receptors’ fundamental role in animal development, important insights on their mechanisms have been gained through studies in model systems, including Drosophila melanogaster and Caenorhabditis elegans. With receptor dysregulation and activation underlying their role in cancer, molecules that inhibit EGFR/ErbB activity are of particular interest. One such inhibitory molecule is Kekkon1 (Kek1), the founding member of the Drosophila family of leucine-rich repeats (LRR) and immunoglobulin domain (Ig) containing proteins. The LIG superfamily is characterized by their unique extracellular regions where LRRs and Ig domains are expressed in tandem. In Kek1, the LRRs and transmembrane region have been shown to be critical for its ability to bind and inhibit the Drosophila EGF receptor (dEGFR). In addition, it has been reported that Kek1 is able bind to and inhibit the mammalian ErbB receptors. This latter report is perplexing since Domain V of dEGFR, an extracellular domain absent in the mammalian ErbB receptors, has been implicated in Kek1 binding and inhibition. To resolve this, in this thesis the ability of Kek1 to interact with the human EGFR/ErbB receptors and dEGFR was examined in greater detail. Using wild-type proteins, as well as protein chimeras and variants, Kek1 was shown to interact uniquely with dEGFR and not with the human EGFR/ErbB receptors. This work also demonstrates that Domain V of dEGFR is necessary for Kek1 binding. Finally, these results implicate differences between the Drosophila and human receptors in module 6 of Domain IV in restricting the interaction to the Drosophila receptor. Taken together, my results support a model whereby Kek1 binds the Drosophila, not the human receptors, and specificity occurs principally through Domain V, a domain lacking in the human receptors. This provides deeper insight to the structural requirements underlying Kek1’s interaction with dEGFR and has clear implications for the proposed use of Kek1 as a therapeutic.
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