Physiological Roles of the XB130/Tks5 Scaffold Protein Interaction for the Regulation of Cell Homeostasis
Year: 2016
Type: dissertation
Abstract: XB130 is a scaffold protein that regulates cell growth, survival and migration by forming dynamic complexes with other proteins that mediate signal transduction cascades for the regulation of cell function. Yeast two-hybrid screening identified another scaffold protein, tyrosine kinase substrate 5 (Tks5), as XB130’s top putative binding partner. We hypothesized that as scaffold proteins, XB130 and Tks5 interact to facilitate the formation of distinct molecular complexes for the mediation of signal transduction, which is required for the regulation of cellular processes, like growth, survival and migration for cell homeostasis. In the present study, we characterized the structural interaction between XB130 and Tks5 by demonstrating that XB130 N-terminal polyproline rich motifs bind to a WWY ligand binding motif in the 5th SH3 domain of TKS5. Tks5 is a well studied protein in cell migration processes. This study demonstrated that Tks5 plays a role in cell proliferation and survival of airway epithelial cells. Additionally, the XB130/Tks5 interaction was shown to regulate cell proliferation, growth and survival via EGFR/Src/PI3K signaling. Surprisingly, we discovered that XB130 and TKS5 play contrasting roles in cell migration; XB130 promotes lamellipodia formation and lateral cell migration, whereas TKS5 promotes podosome formation and extracellular matrix degradation for cell invasion. Consequently, XB130 was shown to dissociate from TKS5 to interact with Rac1 for the assembly and activation of the Rac1/PAK/WAVE2 lamellipodia pathway, whereas, Tks5 mediates the Cdc42/PAK/N-WASP podosome pathway for regulation of stimulus-dependent cytoskeletal rearrangement and cell morphology changes. In conclusion, the dynamic relationship between XB130 and TKS5 facilitates distinct protein-protein interactions and complex formation for the mediation of signal transduction and regulation of cell proliferation, survival and motility. Our data suggests that these dynamic scaffold protein interactions may be a common mechanism for proteins to form unique signaling complexes that facilitate the regulation or enhancement of different physiological or pathophysiological conditions.
Source: TSpace (University of Toronto)
Author: Serisha Moodley
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3156041782