Conservation and Function of the N terminal Insert of Kek1

Patten, Josephine

Student Work

Conservation and Function of the N terminal Insert of Kek1

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The Epidermal growth factor receptor (EGFR/ErbBs) is a receptor tyrosine kinase that is associated with many cancers because of its role in cell proliferation, survival, migration, and determination (Wieduwilt & Moasser, 2008). Previously, a protein, Kekkon1 (Kek1), has been discovered as an inhibitor of Drosophila EGFR (dEGFR). Kek1 is a member of the Kekkon (Kek) family which contains six LIG family members. It’s previously been found that only the extracellular and transmembrane are needed to cause inhibition of dEGFR (Alvarado et al., 2004). The extracellular region consists of N-flank, seven LRRs, C-flank and Ig domain, however, only Kek1 contains a N-insert prior to the N-flank (Alvarado et al., 2004). Since the rest of the Kek family doesn’t bind to the dEGFR, one model is that the N-insert specifies binding. To test this, a phylogenetic analysis of N-insert of Kek1 orthologs was performed to identify conserved regions. Secondly, variants eliminating the N-insert, Kek1ΔN, were generated and tested for dEGFR binding. Lastly, in silico models of the Kek1/dEGFR complex were generated to examine a role for the N-insert in binding. Together, the data support steric hindrance by the N-insert leading to weaker binding and that deletion of the N-insert could increase binding affinity and inhibition. Such insight to the mechanism of inhibition of a receptor tyrosine kinase family member by Kek1 could provide novel paths for the development of cancer therapeutics.

This report represents the work of one or more WPI undergraduate students submitted to the faculty as evidence of completion of a degree requirement. WPI routinely publishes these reports on its website without editorial or peer review.

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