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What we do

Our work combines “small-scale biology” of protein molecular mechanisms and “large-scale” network biology. We seek to answer how structural and biochemical properties of ultrasensitive regulatory switches, such as GTPase conformations or protein phosphorylation, encode for simultaneous, yet precise, regulation of many different cellular processes. We approach these questions with systems biochemistry – a study of protein properties that only become apparent once the protein is studied in the context of the whole cellular network.

Specifically, we use CRISPR-based genome editing methods (e.g., prime editing) to introduce mutations that differentially perturb biochemical properties of regulatory switches. These mutations, e.g., perturb the switch kinetics of GTPases, or the negative feedback regulation of kinases. To obtain a systems-level, quantitative map of how the different mutations affect cellular functions, we use CRISPR/Cas9-based genetic interaction screens. These screens quantify the growth fitness of each point mutant tens of thousands of times, each in the context of an expression perturbation of a different human gene. Genetic interaction screens are a method for unbiased and quantitative measurement of phenotype and a resulting genetic interaction map of a mutation identifies genes involved in all cellular processes that are perturbed by that specific mutation.

There are currently two main research directions in the lab: i) on the functional multi-specificity of RAN GTPase; and ii) on the functional crosstalk between EGF and insulin signaling.