Benjamin Turk, PhD
Research & Publications
The goal of our research is to understand the molecular mechanisms underlying cellular phosphorylation networks, and how these 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 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
Pharmacology; Protein Kinases; Protein Engineering; Peptide Library; Proteomics; Molecular Mechanisms of Pharmacological Action; Carcinogenesis
- Proteome-wide screening for mitogen-activated protein kinase docking motifs and interactorsShi G, Song C, Torres Robles J, Salichos L, Lou H, Lam T, Gerstein M, Turk B. Proteome-wide screening for mitogen-activated protein kinase docking motifs and interactors Science Signaling 2023, 16: eabm5518. PMID: 36626580, PMCID: PMC9995140, DOI: 10.1126/scisignal.abm5518.
- An atlas of substrate specificities for the human serine/threonine kinomeJohnson J, Yaron T, Huntsman E, Kerelsky A, Song J, Regev A, Lin T, Liberatore K, Cizin D, Cohen B, Vasan N, Ma Y, Krismer K, Robles J, van de Kooij B, van Vlimmeren A, Andrée-Busch N, Käufer N, Dorovkov M, Ryazanov A, Takagi Y, Kastenhuber E, Goncalves M, Hopkins B, Elemento O, Taatjes D, Maucuer A, Yamashita A, Degterev A, Uduman M, Lu J, Landry S, Zhang B, Cossentino I, Linding R, Blenis J, Hornbeck P, Turk B, Yaffe M, Cantley L. An atlas of substrate specificities for the human serine/threonine kinome Nature 2023, 613: 759-766. PMID: 36631611, PMCID: PMC9876800, DOI: 10.1038/s41586-022-05575-3.
- Tousled-like kinase 2 targets ASF1 histone chaperones through client mimicrySimon B, Lou HJ, Huet-Calderwood C, Shi G, Boggon TJ, Turk BE, Calderwood DA. Tousled-like kinase 2 targets ASF1 histone chaperones through client mimicry Nature Communications 2022, 13: 749. PMID: 35136069, PMCID: PMC8826447, DOI: 10.1038/s41467-022-28427-0.
- PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEKCho E, Lou HJ, Kuruvilla L, Calderwood DA, Turk BE. PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK Cell Reports 2021, 34: 108928. PMID: 33789117, PMCID: PMC8068315, DOI: 10.1016/j.celrep.2021.108928.
- Comprehensive profiling of the STE20 kinase family defines features essential for selective substrate targeting and signaling outputMiller 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. PMID: 30897078, PMCID: PMC6445471, DOI: 10.1371/journal.pbio.2006540.
- Homing in: Mechanisms of Substrate Targeting by Protein KinasesMiller CJ, Turk BE. Homing in: Mechanisms of Substrate Targeting by Protein Kinases Trends In Biochemical Sciences 2018, 43: 380-394. PMID: 29544874, PMCID: PMC5923429, DOI: 10.1016/j.tibs.2018.02.009.
- Rational Redesign of a Functional Protein Kinase-Substrate InteractionChen 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. PMID: 28314095, PMCID: PMC5442603, DOI: 10.1021/acschembio.7b00089.
- Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β–dependent mechanismsShi 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-e4566. PMID: 27432991, PMCID: PMC4978292, DOI: 10.1073/pnas.1608319113.
- Identification of a Major Determinant for Serine-Threonine Kinase Phosphoacceptor SpecificityChen 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 2013, 53: 140-147. PMID: 24374310, PMCID: PMC3898841, DOI: 10.1016/j.molcel.2013.11.013.