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The kinetics of receptor tyrosine kinase (RTK) signaling

The Mudumbi lab is fundamentally interested in the mechanistic underpinnings of signal transduction by cell surface transmembrane receptors. This is a central question at the heart of understanding how cells receive and interpret signals from the outside environment to achieve different downstream cellular outcomes. The lab is currently focused on the receptor tyrosine kinase (RTK) family of single-pass transmembrane cell surface receptors, which play a crucial role in nearly every biological process in mammals, including proliferation, differentiation, metabolism, and apoptosis. Dysregulation of RTKs underlies many diseases including cancer, diabetes, and bone disorders to name a few. Of particular interest, a number of single-pass transmembrane receptors exhibit biased signaling – where different ligands specify completely distinct signals through the same receptor.

It is increasingly clear that the static structural views provided by crystallography and cryo-EM cannot explain biased signaling or the effects of oncogenic mutations. Specification of cellular outcomes appears to depend on precise signaling kinetics in the cell, and a dynamic view of the receptor ‘in action’ will be crucial for understanding this. Furthermore, understanding signaling dynamics will also open up the exciting possibility of developing biologics (e.g. antibodies or altered ligands) that can ‘fine-tune’ signaling outcomes, instead of simply shutting down aberrant signaling.

To tackle this challenge, the Mudumbi lab uses a number of state-of-the-art imaging-based approaches that allows us to directly observe and understand the dynamics of individual receptors – at the single-molecule level – in living cells.