Benjamin Turk, PhD
Cards
Education
Massachusetts Institute of Technology (1999)
Oberlin College (1990)
Additional Titles
Director of Medical Studies, Pharmacology
Contact Info
Pharmacology
PO Box 208066, 333 Cedar Street
New Haven, CT 06520-8066
United States
Education
Massachusetts Institute of Technology (1999)
Oberlin College (1990)
Additional Titles
Director of Medical Studies, Pharmacology
Contact Info
Pharmacology
PO Box 208066, 333 Cedar Street
New Haven, CT 06520-8066
United States
Education
Massachusetts Institute of Technology (1999)
Oberlin College (1990)
Additional Titles
Director of Medical Studies, Pharmacology
About
Titles
Professor of Pharmacology
Director of Medical Studies, Pharmacology
Appointments
Pharmacology
ProfessorPrimary
Other Departments & Organizations
Education & Training
- Postdoc
- Harvard Medical School (2004)
- PhD
- Massachusetts Institute of Technology (1999)
- BA
- Oberlin College (1990)
Research
Overview
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 human genome encodes over 500 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 human kinases. 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 cancer-associated kinase mutations and treatment with kinase inhibitor drugs lead to "re-wiring" of phosphorylation networks. We are also developing new methodology to identify short linear motifs (SLiMs) in substrates and other interactors that bind to grooves and pockets outside of the kinase catalytic cleft. One outcome of this work is the identification of new strategies and agents for pharmacological targeting of signaling pathways relevant to disease.
Medical Research Interests
ORCID
0000-0001-9275-4069- View Lab Website
Turk Lab
Research at a Glance
Research Interests
Protein Kinases
Signal Transduction
Mitogen-Activated Protein Kinases
Peptide Library
Proteomics
Carcinogenesis
Publications
Featured Publications
Distinct functional constraints driving conservation of the cofilin N-terminal regulatory tail
Sexton J, Potchernikov T, Bibeau J, Casanova-Sepúlveda G, Cao W, Lou H, Boggon T, De La Cruz E, Turk B. Distinct functional constraints driving conservation of the cofilin N-terminal regulatory tail. Nature Communications 2024, 15: 1426. PMID: 38365893, PMCID: PMC10873347, DOI: 10.1038/s41467-024-45878-9.Peer-Reviewed Original ResearchMeSH Keywords and ConceptsConceptsN-terminal regionActin bindingSequence requirementsLIM kinaseAnalysis of individual variantsInactivates cofilinS. cerevisiaeRegulatory tailFamily proteinsActin depolymerizationPhosphorylation sitesKinase recognitionSequence variantsInhibitory phosphorylationCofilinN-terminusIndividual variantsFunctional constraintsActinDisordered sequencesPhosphorylationSequenceBiochemical analysisSequence constraintsKinaseLinear motif specificity in signaling through p38α and ERK2 mitogen–activated protein kinases
Robles J, Lou H, Shi G, Pan P, Turk B. Linear motif specificity in signaling through p38α and ERK2 mitogen–activated protein kinases. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2316599120. PMID: 37988460, PMCID: PMC10691213, DOI: 10.1073/pnas.2316599120.Peer-Reviewed Original ResearchMeSH Keywords and ConceptsConceptsExtracellular signal-regulated kinase 2Docking motifERK2 mitogen-activated protein kinaseSignal-regulated kinase 2Protein kinase cascadeMitogen-activated protein kinaseFull-length proteinMAPK substratesEukaryotic cellsKinase cascadeMAPK networkLinear motifsProtein kinaseMotif specificityProteomic librariesDocking siteAcidic residuesKinase 2Diverse stimuliCellular responsesP38αDocking interfaceHigh net chargeMotifSelective interactionAn atlas of substrate specificities for the human serine/threonine kinome
Johnson 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.Peer-Reviewed Original ResearchMeSH Keywords and ConceptsConceptsSer/ThrHuman Ser/ThrSubstrate specificityPhosphorylation eventsProtein serine/threonine kinaseWidespread post-translational modificationSerine/threonine kinasePutative protein kinaseSubstrate sequence specificityIntrinsic substrate specificityPost-translational modificationsThreonine phosphorylationGenetic perturbationsThreonine kinasePhosphorylation sitesHuman genomeProtein phosphorylationProtein kinaseSequence specificityBiological pathwaysHuman diseasesNegative selectivityKinaseUnexpected insightsKinomeProteome-wide screening for mitogen-activated protein kinase docking motifs and interactors
Shi 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.Peer-Reviewed Original ResearchMeSH Keywords and ConceptsConceptsMitogen-activated protein kinaseDocking motifSequence motifsDocking sequenceShort linear sequence motifsLinear sequence motifsSubstrate recruitmentHuman proteomeProtein kinaseCatalytic cleftExchange mutantsEssential functionsCultured cellsScreening pipelineWide screeningInteractorsMotifSequenceLimited repertoireSelective bindingInteractomeCombinatorial librariesMKK6ProteomeMKK7Homing 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. PMID: 29544874, PMCID: PMC5923429, DOI: 10.1016/j.tibs.2018.02.009.Peer-Reviewed Original ResearchMeSH Keywords and ConceptsConceptsProtein kinaseReversible post-translational modificationKinase substrate specificityCellular signaling networksPost-translational modificationsSimilar catalytic domainsMode of regulationSignaling outputsSubstrate repertoireSubstrate targetingSignaling networksPhosphorylation sitesProtein phosphorylationCatalytic domainSubstrate specificityKinaseCell behaviorEukaryotesRecent progressPhosphorylationAnticancer drugsSitesRegulationMechanismTargetingThe intrinsic substrate specificity of the human tyrosine kinome
Yaron-Barir T, Joughin B, Huntsman E, Kerelsky A, Cizin D, Cohen B, Regev A, Song J, Vasan N, Lin T, Orozco J, Schoenherr C, Sagum C, Bedford M, Wynn R, Tso S, Chuang D, Li L, Li S, Creixell P, Krismer K, Takegami M, Lee H, Zhang B, Lu J, Cossentino I, Landry S, Uduman M, Blenis J, Elemento O, Frame M, Hornbeck P, Cantley L, Turk B, Yaffe M, Johnson J. The intrinsic substrate specificity of the human tyrosine kinome. Nature 2024, 629: 1174-1181. PMID: 38720073, PMCID: PMC11136658, DOI: 10.1038/s41586-024-07407-y.Peer-Reviewed Original ResearchConceptsIntrinsic substrate specificityTyr kinasesTyr sitesSequence specificityProtein Tyr kinasesSubstrate sequence specificitySites of phosphorylationPhosphorylation of proteinsMulticellular eukaryotesMetazoan organismsMotif preferencesPhosphoproteomic datasetsSubstrate sequenceTyrosine (Tyr) residuesKinase specificityPattern of residuesSubstrate specificitySignaling networksYears of evolutionPeptide arraysTyrosine kinomeAnti-cancer drugsOncogenic variantsTyr residuesKinase
2024
Setdb1-loss induces type-I interferons and immune clearance of melanoma.
McGeary M, Damsky W, Daniels A, Lang S, Xu Q, Song E, Huet-Calderwood C, Lou H, Paradkar S, Micevic G, Kaech S, Calderwood D, Turk B, Yan Q, Iwasaki A, Bosenberg M. Setdb1-loss induces type-I interferons and immune clearance of melanoma. Cancer Immunology Research 2024 PMID: 39589394, DOI: 10.1158/2326-6066.cir-23-0514.Peer-Reviewed Original ResearchConceptsT cell infiltrationMHC-I expressionType I interferonImmune clearanceCD8+ T cell-dependent mannerIncreased CD8+ T cell infiltrationCD8+ T cell infiltrationDecreased MHC-I expressionAnti-cancer immune responseT cell-dependent mannerCD8+ T cellsDecreased T-cell infiltrationComplete tumor clearanceImmunity to melanomaIncreased melanoma growthInflamed tumor microenvironmentLoss of SETDB1Type I interferon receptorTreatment of melanomaType I interferon signalingWhole-genome CRISPR screenEndogenous retrovirusesType I interferon expressionMetastatic diseaseTumor clearanceAurora B controls anaphase onset and error-free chromosome segregation in trypanosomes
Ballmer D, Lou H, Ishii M, Turk B, Akiyoshi B. Aurora B controls anaphase onset and error-free chromosome segregation in trypanosomes. Journal Of Cell Biology 2024, 223: e202401169. PMID: 39196069, PMCID: PMC11354203, DOI: 10.1083/jcb.202401169.Peer-Reviewed Original ResearchMeSH Keywords and ConceptsConceptsAurora BAnaphase onsetMetaphase-to-anaphase transitionPromote mitotic exitComplex regulatory circuitryEarly-branching eukaryotesKinetochore-microtubule attachmentsAurora B activityDelays anaphase onsetAurora B kinaseCell cycle progressionSpindle assembly checkpointKinetochore proteinsMitotic exitOuter kinetochoreChromosome segregationChromosome missegregationRegulatory circuitrySpindle microtubulesAurora B inhibitionCycle progressionTrypanosoma bruceiAssembly checkpointB kinaseKinetochore
2023
Autoregulation of the LIM kinases by their PDZ domain
Casanova-Sepúlveda G, Sexton J, Turk B, Boggon T. Autoregulation of the LIM kinases by their PDZ domain. Nature Communications 2023, 14: 8441. PMID: 38114480, PMCID: PMC10730565, DOI: 10.1038/s41467-023-44148-4.Peer-Reviewed Original Research
2022
Tousled-like kinase 2 targets ASF1 histone chaperones through client mimicry
Simon 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.Peer-Reviewed Original ResearchMeSH Keywords and ConceptsMeSH KeywordsAmino Acid MotifsAmino Acid SequenceCatalytic DomainCell Cycle ProteinsConserved SequenceCrystallography, X-RayHistonesHumansMolecular ChaperonesMolecular Docking SimulationMolecular MimicryMutagenesisPeptide LibraryPhosphorylationProtein KinasesRecombinant ProteinsSubstrate SpecificityConceptsTousled-like kinaseDNA replication-coupled nucleosome assemblyNuclear serine-threonine kinaseReplication-coupled nucleosome assemblyHistone chaperone proteinsGlobular N-terminal domainProper cell divisionPhosphorylation site motifsSerine-threonine kinaseShort sequence motifsAsf1 histone chaperonesC-terminal tailN-terminal domainHistone chaperonesGenome maintenanceNucleosome assemblySequence motifsChaperone proteinsNon-catalytic interactionsCatalytic domainCell divisionSite motifN-terminusStringent selectivityCell growth
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Pharmacology
PO Box 208066, 333 Cedar Street
New Haven, CT 06520-8066
United States