Research interests

Eukaryotic cells use signaling pathways to control their responses to specific extracellular cues.  The goal of our research is to understand the molecular mechanisms underlying these pathways and how they are organized into larger networks.  Our studies focus on protein-modifying enzymes, in particular protein kinases and proteases, that are key players in signaling.  We use a combination of molecular diversity approaches (peptide arrays, phage display, small molecule screening) and conventional cell and molecular biology to understand the mechanisms of substrate recognition by these enzymes and to probe how substrate specificity impacts biological function. One outcome of this work is the identification of new strategies and agents for pharmacological targeting of pathways relevant to disease.

Protein kinases in cell growth and survival.  Protein kinases are critical intermediates in signaling pathways controlling cell proliferation and survival, and aberrant kinase activity frequently contributes to the development of cancer. We use peptide and protein library screening to identify consensus amino acid sequences targeted by kinases involved in these pathways.  These studies provide fundamental insight into how the kinases recognize and achieve specificity for their target substrates.  This understanding helps us to identify novel protein substrates through bioinformatics and to discover new small molecule kinase inhibitors.

Kinomics. We have recently developed a high-throughput peptide screening method for determining protein kinase phosphorylation motifs.  In collaboration with Mike Snyder’s lab in the MCDB department, we have undertaken a large scale screening effort to determine consensus phosphorylation sequences for every protein kinase produced by the budding yeast S. cerevisiae. The broad goal of this work is to define the yeast phosphorylation signaling network through proteome-wide identification of new phosphorylation sites.

Metalloproteinases in signaling.  In mammals, signaling through the epidermal growth factor receptor (EGFR or ErbB) tyrosine kinase family is a nearly universal mechanism for promoting cell proliferation and survival.  Ligands for the EGFR family are produced as transmembrane precursors that are inducibly processed to their soluble, active forms.  The enzymes responsible for cleaving the ligands belong to a large family of cell surface metalloproteinases called ADAMs.  We are interested in understanding the mechanisms by which ADAMs discriminate among the different EGFR ligands, and how these proteases are activated by extracellular signals.

Blocking anthrax toxin.  Antibiotics fail as therapy for inhalational anthrax because the bacteria produce a secreted toxin that is the direct cause of death.  The active component of this toxin is a metalloproteinase called lethal factor that specifically cleaves MAP kinase kinases, thereby shutting off signaling pathways important for cell survival and host defense against infection.  We are studying how lethal factor interacts with these kinases as a means to elucidate mechanisms of toxin-mediated cell death and to design inhibitors to be used as anti-anthrax drugs.

TURK LAB Yale University