To understand the mechanisms of receptor mediated signaling, the Mudumbi lab combines cutting-edge live cell imaging techniques \u2013 single-particle tracking (SPT), single-molecule F\u00f6rster resonance energy transfer (smFRET), super-resolution microscopy, and single-cell FRET to name a few \u2013 with a number of other biochemical and molecular biology approaches (phosphoproteomics, signaling assays, etc). The research in the Mudumbi lab has two main focuses: 1) receptor activation kinetics and 2) downstream signaling kinetics. By understanding the kinetics of signal transduction from the level of both receptor signaling and downstream events, we hope to build a \u2018kinetic landscape\u2019 to understand how receptors achieve distinct signaling responses through the same receptor. This will allow us to target these kinetics with therapeutics and modulate or \u2018fine-tune\u2019 them for specific cellular outcomes.<\/p>\n
Receptor Activation Kinetics<\/strong><\/p>\n Several receptor tyrosine kinases (RTKs) have multiple different activating ligands that can elicit distinct signaling outcomes by activating the same receptor, a phenomenon known as biased signaling. A prime example of this is the epidermal growth factor receptor (EGFR), an RTK in the ErbB family of receptors, which has 7 different activating ligands (EGF, TGF\u03b1, BTC, HB-EGF, EREG, EPGN, and AREG). Work from several labs (Freed Cell 2017, Kim Cell 2017, Ho Cell 2017, Huang Cell Rep. 2017) has started to suggest that receptor activation kinetics likely controls the biased signaling exhibited by these receptors, and that mutations can alter both a receptor\u2019s affinity for different ligands as well as its dimerization kinetics. The Mudumbi lab has developed tools to directly observe and quantitate the dimerization kinetics of receptors in living cells. Focusing on the ErbB family of receptors, we are interested in studying receptor dimerization kinetics, and how these kinetics are altered by different activating ligands and mutations. We are also very interested in studying how dimerization kinetics are altered to modulate signaling by heterodimerization.<\/p>\n