[PINN 1-17] Hosted by John Fu, Ben Turk, PhD, is an Associate Professor of Pharmacology, School of Medicine, Yale University, New Haven, CT
Deciphering mechanisms of substrate targeting by protein kinases
The completion of the human genome a decade ago revealed more than 500 genes encoding protein kinases, and mass spectrometry based phosphoproteomics efforts have now cataloged over 100,000 sites of phosphorylation in mammalian cells. These studies have clearly outpaced our ability to understand signaling networks through analysis of individual kinases and their substrates: for the vast majority of the phosphorylation sites, the responsible kinase and functional significance are simply not known. My group studies basic mechanisms used by kinases to target specific substrates within the cell, with the idea of applying this knowledge to identify new kinase-substrate pairs on a proteomic scale. Kinases interact with their substrates through short sequence motifs found both at the site of phosphorylation and at distal sites. We develop methodology that allows for the rapid identification of these protein kinase recognition motifs. Using synthetic peptide arrays, we have recently conducted a biochemical screen to identify phosphorylation site motifs recognized by the entire set of kinases from budding yeast, and a similar screen of the human kinome is in progress. Information from these screens is used to map cellular phosphorylation networks and to relate mechanisms of substrate targeting to specific structural features of kinases.