The Phylogenetic Functional Conservation of  <i>Drosophila</i> Seven-in-Absentia (SINA) E3 Ligase and Its Two Human Paralogs, SIAH1 and SIAH2, in  <i>Drosophila</i> Eye Development

Abstract

Seven-IN-Absentia (SINA) is the most downstream signaling gatekeeper identified in the Drosophila RAS/EGFR signaling pathway. Underscoring the central importance of Drosophila SINA and human SINA homologs (SIAHs) is its phylogenetic conservation across metazoans. SIAH is a major tumor vulnerability in human cancer. To further delineate the SINA function in Drosophila, a genetic modifier screen was conducted, and 28 new sina mutant alleles were isolated. By sequencing analyses, we identified three invariable amino acid residues in SINA’s RING-domain whose single point mutation ablates SINA function . To demonstrate the functional conservation of this medically important family of RING domain E3 ligases, we compared expression of either wild type (WT) or proteolysis-deficient (PD) SINA/SIAH inhibitors of Drosophila SINAWT/PD and human SIAH1WT/PD /2WT/PD under tissue-specific GAL4-drivers in Drosophila. Our results showed that Drosophila SINA and human SIAH1/2 are functionally conserved. The SINAPD/SIAHPD inhibitors are effective in blocking the RAS-dependent neuronal cell fate determination in Drosophila.