Research Summary

Our lab studies the fundamental changes in the signal transduction pathways in three rather different research areas:

I). Regulated Proteolysis in the RAS Signal Transduction Pathway

II). Toxins, Signal Transduction and Drug Resistance

III). Innate Immunity and Cellular Defense

Our interests can be broadly defined as using the molecular genetic, cellular and biochemical, genomic and developmental approaches to characterize the molecular signaling pathways that control these fundamental biological processes using the model organism Drosophila melanogaster.

Regulated Proteolysis in the RAS Signal Transduction Pathway.

RAS proteins are evolutionarily conserved small GTPases that relay signals from receptor tyrosine kinases (RTKs) to the nucleus to execute specific developmental programs required for cell differentiation, proliferation and apoptosis in all multicellular organisms. Constitutively active forms of RAS are oncogenic and are among the most common genetic alterations in human cancers (approximately 30% of human cancer). Thus an important goal in cancer biology is to understand the molecular mechanisms underlying normal and aberrant RAS signals. Many key components and aspects of the RAS signaling pathway are evolutionarily conserved. Drosophila R7 photoreceptor cell fate specification is a genetically tractable model system in which to study RAS signal transduction. In this system, we have shown that RAS activation directs a ubiquitin-mediated proteolysis pathway mediated by SEVEN-IN-ABSENTIA (SINA). SINA encodes a member of a highly conserved family of E3 ubiquitin ligases and has been implicated in neuronal differentiation, apoptosis, stress response, tumor suppression, b-catenin, APC and p53 signaling in vertebrates. The substrate specificity of ubiquitin-mediated proteolysis is primarily determined by the E3 ligases, and the focus of our research is on the SINA E3 ligase, an essential downstream component of RAS signaling pathway. The objectives of our research projects are (1) to determine the developmental roles and regulation of SINA E3 family-dependent proteolysis in RAS signaling using Drosophila as a model organism, (2) to identify new SINA pathway components and determine their function in regulated proteolysis in RAS signal transduction, and (3) to investigate the roles of the mammalian SINA homologues (SIAHs) in RAS-mediated oncogenesis and to elucidate how the SIAH-dependent proteolysis promotes cell growth, differentiation and apoptosis during animal development and human cancers. Since many known SINA substrates have a demonstrated role in oncogenesis, it is likely that our research efforts will identify novels targets for anticancer therapies and contribute to our understanding of cancer biology.

Toxins, Signal Transduction and Drug Resistance

A second research area that we are interested in is understanding the signal transduction events involved in controlling drug/chemical resistance development, including anticancer drug resistance. The development of organisms or cells resistant to drug is a recurring problem in medicine. There is an important need for us to understand the mechanisms by which many important anticancer drugs work, and by which drug resistance is acquired. While it is extremely straightforward to carry out genetic screens for drug resistance in Drosophila, such screens have not been carried out to date. We will carry out genetic screens for resistance to several medically important anticancer drugs that are prone to develop drug resistance. This effort, coupled with DNA microarray analyses, should help to identify the signaling pathways through which these compounds work and are detoxified. Given the ample examples of conservation between fly and vertebrate developmental strategies, insights into the underlying logic of signal transduction pathways that give rise to chemical resistance gained from studies in Drosophila should broaden our understanding of the molecular mechanisms of drug/chemical resistance in general.

Innate Immunity and Cellular Defense

Drosophila has an innate immune system that is similar to humans. We will use flies to study the role that innate immunity plays in cytoprotection and accommodation in order to develop new and better approaches in transplant medicine.