Research

Perturbations to cell signaling and receptor trafficking in the context of EGFR mutation.

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that drives signaling processes involved in proliferation, survival, and migration in cells and tissues throughout the body.  EGFR mutation and over-expression are observed in numerous human malignancies.  Mutations that lead to the constitutive activation of EGFR in lung and brain cancers are of special interest to our lab, in part because these mutations alter the important coupling between receptor trafficking and downstream signaling in ways that ultimately influence cancer cell fates, including response to therapy.  In cancer cells expressing these EGFR mutants, our lab is particularly interested in the functions of two downstream regulators of EGFR-mediated signaling, the protein tyrosine phosphatase SHP2 and the EGFR feedback regulator Sprouty2.

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Quantitative models of receptor-mediated signaling.

Our lab is also involved in the development of mechanistic models of receptor-mediated signaling processes, with a special focus on models of EGFR phosphorylation and trafficking kinetics.  Such models are a useful vehicle for integrating our most recent quantitative cell biological measurements with existing structure-based models of EGFR function to develop new understand of EGFR regulation.  For example, our quantification of the kinetics of EGFR tyrosine dephosphorylation in different cellular compartments have been utilized to develop new experimentally testable predictions for the key determinants of the efficacies of different classes of EGFR-targeted therapeutics and to predict how differences in receptor dimerization schemes observed within the super-family of receptor tyrosine kinases may lead to different modes of signaling regulation for different types of receptors.  We are currently extending our models to develop predictive understanding of the ability of EGFR to regulate the persistence of multi-protein complexes of signaling proteins as a function of time and position within the cell.

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Epithelial-mesenchymal transition.

The cellular developmental process of epithelial-mesenchymal transition (EMT) is hijacked in a number of epithelial-derived cancers to produce cells that with increased potential to metastasize and resist therapy.  Our lab has identified a key role for the ERK signaling pathway in this process and shown that this new understanding can potentially be leveraged to develop new strategies for rationally scheduling different types of therapy to promote overall improved response to therapy.  We are now extending this analysis to study the basis of cooperative signaling through different classes of receptors that produces the most efficient EMT.

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Receptor-mediated processes in the mammalian kidney.

In the human nephron, plasma proteins are ultrafiltered across the glomerular capillary walls and reabsorbed downstream from the lumen of the proximal tubule.  Our lab is actively engaged in studies of how receptors participate in both processes.  In collaboration with colleagues at in the University of Pennsylvania Renal Electrolyte and Hypertension Division, we are studying the signaling network that is activated in podocytes (specialized glomerular epithelial cells) in response to the phosphorylation of nephrin, a receptor expressed at the junction between interdigitating podocytes in the healthy glomerular capillary wall.  In collaboration with Dr. Casim Sarkar (University of Minnesota), we are studying the receptor-mediated reabsorption of albumin in the proximal tubule, in an effort to co-opt this endogenous system to increase the bioavailability of protein-based therapeutics.

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