The JAK/STAT pathway is but one of the signal transduction cascades responsible for proper development and homeostasis. Gain-of-function mutations of pathway components are causative agents of several leukemias, highlighting the necessity for proper regulation of signal transduction. Drosophila presents an attractive model to study JAK/STAT signaling because mutations in the pathway behave in an analogous manner. Furthermore, the Drosophila cascade is much simpler as only one of each component required for activation has been characterized; whereas in mammals, there are many ligands, receptors, 4 JAKs and 7 STATs.Suppressors of Cytokine Signaling (SOCS) are one family of molecules which regulate JAK/STAT signaling via a negative feedback loop. All SOCS share a distinct modular domain architecture, which we exploited to locate three putative SOCS homologues within the Drosophila genome. I present the identification and initial characterization of one of these homologues, Socs44A. I show that Socs44A is not responsive to or dependent on JAK activity. However, I demonstrate that Socs44A is capable of downregulating JAK/STAT signaling in the developing wing but not inoogenesis, indicating that its ability to regulate the pathway is tissue specific, a phenomenon observed in the mammalian model.Signal transduction pathways are integrated at multiple levels. This interplay allows for combinatorial signaling, resulting in a higher order of complexity in the signals that can be received and interpreted by a cell. Well documented are the interactions between the JAK/STAT and the EGFR/MAPK pathways. In this work, I show that Socs44A can genetically interact with, and upregulate, the EGFR/MAPK pathway, analogous to a recent report involving SOCS-3.Starting with the Drosophila genome sequence, I initiated a reverse genetic approach to studying the function of the Socs44A locus. During the course of this investigation, I designed and implemented a novel post-processor of the BLAST algorithm, called Multi-BLAST, which facilitates retrieval of multiple domain sequences from public databases. In what would have been the ultimate achievement of this study, I attempted two mutagenesis screens designed to isolate Socs44A loss-of-function alleles. Progress on these screens is reported.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:gradschool_diss-1271 |
| Date | 01 January 2004 |
| Creators | Rawlings, Jason Scott |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | University of Kentucky Doctoral Dissertations |
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