Home / People / Alumni / Mark Sevecka

Mark Sevecka

Current position: Scientist, Merrimack

LinkedIn profile

Education

Ph.D., Harvard University, 2008
M.A., Harvard University, 2004
Pre-Diploma, Technical University of Munich, Germany, 2001

Research

The epidermal growth factor receptor (EGFR) and the downstream signaling pathways it activates play important roles in development and as therapeutic targets in the treatment of cancer. My research aims to obtain an understanding of the EGFR network on a system-wide level by applying perturbations throughout the network and measuring the effect on downstream signaling proteins.

To this end, I have developed a high-throughput method that combines the advantages of a cell-based assay with lysate microarray technology. Cells in 96-well microtiter plates are subjected to different perturbations, stimulated with a growth factor and lysed at specific time points. Microarrays of the resulting lysates are then probed with antibodies to determine changes in abundance and phosphorylation levels for a panel of target proteins.

As a first step, I have applied this technology to small molecule profiling. Using a library of 84 kinase and phosphatase inhibitors, I was able to identify groups of signaling proteins that are similarly affected by small molecule treatment. Moreover, the data also revealed groups of compounds that induce common patterns of phosphorylation of downstream proteins. These patterns constitute different states of the ErbB signaling network that match our current understanding of its connectivity, suggesting that small molecule screening can be conducted in a state-based rather than a target-based manner.

I am currently developing a second-generation assay that uses lentiviral-based RNAi to perturb the abundance of signaling proteins rather than their enzymatic activity alone. A comprehensive dataset involving perturbation of a large set of signaling proteins will be used to construct a quantitative, predictive model of EGFR signaling.

Publications

Wolf-Yadlin*, A., Sevecka*, M. & MacBeath, G. Dissecting Protein Function and Signaling Using Protein Microarrays. Manuscript submitted, Curr. Opin. Chem. Biol. (2009).

Gordus, A., Krall, J.A., Beyer, E.M., Kaushansky, A., Wolf-Yadlin, A., Sevecka, M., Chang, B.H., Rush, J. & MacBeath, G. Linear combinations of docking affinities explain quantitative differences in receptor tyrosine kinase signaling. Mol. Syst. Biol. 5:235 (2009).

Sevecka, M. & MacBeath, G. State-based discovery: a multidimensional screen for small-molecule modulators of EGF signaling. Nat. Methods. 3, 825-831 (2006).

Stiffler, M.A., Grantcharova, V.P., Sevecka, M. & MacBeath, G. Uncovering quantitative protein interaction networks for mouse PDZ domains using protein microarrays. J. Am. Chem. Soc. 128, 5913-22 (2006).

Collaborators

Alejandro Wolf-Yadlin, Joel Wagner

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