Tuesday, May 7, 2024
5/7/2024
Project Summary Understanding the molecular mechanisms that shape an effective cellular response is a primary goal in biology. One critical regulator of cell function is the process of signal transduction that enables cells to respond rapidly and specifically to cues in the surrounding environment. These cues can be biochemical or biophysical. The dynamic interplay of signaling partners along signaling pathways and the rapid turnover of post-translational modifications are critical components necessary to create a highly sensitive system. Strict regulation of signal transduction is crucial for normal cellular processes, while unregulated signaling is an important component in the pathogenesis of many diseases. Fundamental gaps remain in our understanding of how protein interactions and dynamics control signaling. The research proposed in this MIRA renewal application seeks to understand the fundamental mechanisms through which biochemical and mechanical cues fine-tune the signaling response. We propose that this fine-tuning is achieved by modulation of dynamic and stochastic behavior of protein-protein interactions that are integrated to produce a specific signaling outcome. The overarching theme of our research is to elucidate how the composition and dynamics of signaling complexes define signaling specificity and outcome. Our central question is that of how multiple membrane receptors collaborate to interpret multiple environmental cues, be they physical or chemical, and how the resulting information is integrated to define the cellular response. To get at these central questions in cell signaling, we initially focus on two signaling systems: FceRI, the primary immunoreceptor on mast cells that is involved in allergy/asthma, and receptor tyrosine kinases (RTKs) that drive oncogenesis. We will determine how FceRI and associated integrins can translate antigen geometry and surrounding substrate stiffness into specific outcomes. We will develop a better understanding of how crosstalk between two RTKs, EGFR and RON, is controlled through the study of the dynamics and composition of EGFR/RON signaling complexes along with the effect of different ligands on complex formation. Parallel study of these two systems allows us to identify conserved mechanisms, enabling us to move the broad field of cellular signal transduction forward in new directions. We use unique and innovative imaging techniques to provide quantitative information on the composition and dynamics of signaling complexes - as they form on intact cells - that cannot be obtained using traditional biochemical or structural techniques. The unique quantitative information that we obtain will address challenging supramolecular questions that have evaded the field thus far, bring new perspectives to cell biological processes and providing new therapeutic understanding.
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