Research Departments & Organizations
The goal of our research is to understand the molecular mechanisms underlying signaling pathways in eukaryotic cells, and how phosphorylation networks are re-wired in cancer cells. 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 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. As an extension of these studies, we are also examining how kinase mutations found in tumor cells can cause changes in substrate specificity or catalytic activity and consequent "re-wiring" of phosphorylation networks. We are also developing new methodology to identify “docking” motifs in substrates that interact with grooves and pockets outside of the kinase active site. One outcome of this work is the identification of new strategies and agents for pharmacological targeting of signaling pathways relevant to disease.
Specialized Terms: Cell signaling; Protein kinases; Chemical biology; Proteomics; Protein engineering; Cancer signaling networks
Homing in: Mechanisms of Substrate Targeting by Protein Kinases.
Miller CJ, Turk BE. Homing in: Mechanisms of Substrate Targeting by Protein Kinases. Trends In Biochemical Sciences 2018, 43:380-394. 2018
Comprehensive profiling of the STE20 kinase family defines features essential for selective substrate targeting and signaling output.
Miller CJ, Lou HJ, Simpson C, van de Kooij B, Ha BH, Fisher OS, Pirman NL, Boggon TJ, Rinehart J, Yaffe MB, Linding R, Turk BE. Comprehensive profiling of the STE20 kinase family defines features essential for selective substrate targeting and signaling output. PLoS Biology 2019, 17:e2006540. 2019
Substrate priming enhances phosphorylation by the budding yeast kinases Kin1 and Kin2.
Jeschke GR, Lou HJ, Weise K, Hammond CI, Demonch M, Brennwald P, Turk BE. Substrate priming enhances phosphorylation by the budding yeast kinases Kin1 and Kin2. The Journal Of Biological Chemistry 2018, 293:18353-18364. 2018
Rational Redesign of a Functional Protein Kinase-Substrate Interaction.
Chen C, Nimlamool W, Miller CJ, Lou HJ, Turk BE. Rational Redesign of a Functional Protein Kinase-Substrate Interaction. ACS Chemical Biology 2017, 12:1194-1198. 2017
Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms.
Shi X, Mihaylova VT, Kuruvilla L, Chen F, Viviano S, Baldassarre M, Sperandio D, Martinez R, Yue P, Bates JG, Breckenridge DG, Schlessinger J, Turk BE, Calderwood DA. Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113:E4558-66. 2016
Identification of a major determinant for serine-threonine kinase phosphoacceptor specificity.
Chen C, Ha BH, Thévenin AF, Lou HJ, Zhang R, Yip KY, Peterson JR, Gerstein M, Kim PM, Filippakopoulos P, Knapp S, Boggon TJ, Turk BE. Identification of a major determinant for serine-threonine kinase phosphoacceptor specificity. Molecular Cell 2014, 53:140-7. 2014