Date of Award
Level of Access Assigned by Author
Doctor of Philosophy (PhD)
Biochemistry and Molecular Biology
Second Committee Member
Robert E. Gundersen
Third Committee Member
Mammalian Sprouty (Spry) genes function to regulate Receptor Tyrosine Kinase (RTK) activity by either inhibiting or activating mitogen activated protein kinase (MAPK) signal transduction. Spry2 inhibits fibroblast growth factor (FGF)-dependent extracellular regulated kinase (ERK) phosphorylation and thus acts as a feedback inhibitor of FGF signaling. The kinase responsible for the tyrosine phosphorylation of Spry2 has been poorly understood, despite the role it plays on Spry2 protein stability and function. To date, the only known method of Spry2 phosphorylation is by activation of either the epidermal growth factor receptor (EGFR) or FGF receptor (FGFR). The conserved N-terminal tyrosine at residue 55 on Spry2 is necessary for its interaction with c-Cbl, an E3 ubiquitin ligase, leading to Spry2 proteosomal degradation and allowing for FGF-induced ERK phosphorylation. Subsequent experiments to determine the kinase responsible for Spry2 tyrosine phosphorylation have identified Src kinase. It was discovered that there is a tyrosine phosphorylated on the C-terminus (Tyr227) that when mutated, ablates the inhibitory effect of Spry2 on endothelial cell activity in vitro. Additionally, Spry2 was shown to interact with seven in absentia homologue 2 (SIAH2), an E3 ubiquitin ligase, which regulates stability and FGF-induced ERK phosphorylation, in a phosphotyrosine independent manner. Together, the data identify Src kinase as responsible for Spry2 tyrosine phosphorylation, the newly identified Tyr227 is phosphorylated by Src kinase and inhibits MAPK activity, and SIAH2 is able to regulate Spry2 stability and function in a phosphotyrosine independent manner.
Nadeau, Robert J., "Sprouty Regulation of Tyrosine Kinase Signal Transduction is Governed by Tyrosine Phosphorylation: A Functional Role for Sprouty2 N- and C- Terminal Tyrosines" (2006). Electronic Theses and Dissertations. 786.