Kathryn M. Ferguson, PhD
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Member, Yale Cancer Biology Institute
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Appointments
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Member, Yale Cancer Biology Institute
Contact Info
Appointments
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Member, Yale Cancer Biology Institute
Contact Info
About
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Associate Professor of Pharmacology
Member, Yale Cancer Biology InstituteBiography
Dr. Ferguson’s research focuses on extracellular control of receptor tyrosine kinases (RTKs), aberrant activation of which can drive cancer and other diseases. Dr. Ferguson obtained her Ph.D. from Yale in 1996, and completed postdoctoral training at the University of Pennsylvania Perelman School of Medicine. She transitioned to an independent faculty position in the Department of Physiology at UPenn in 2003, returning to Connecticut in 2015 to join the Yale Cancer Biology Institute and Department of Pharmacology.
Appointments
Pharmacology
Associate Professor TenurePrimary
Other Departments & Organizations
Education & Training
- PhD
- Yale University, Chemistry (1996)
- BA
- University of Oxford, Physics (1987)
Research
Overview
Mechanisms of activation of RTKs that are dimeric in the unliganded state:
For most (if not all) RTKs, regulation involves more than simple ligand-induced dimerization. In some cases, RTKs form dimers in the absence of ligand so activation must proceed by some alternate mechanism. The insulin receptor (IR), for example, is a disulfide-bonded dimer that is regulated by ligand induced conformational changes. We are interested in the regulation of RTKs that form non-covalent inactive dimers, such at Tie2, that forms an unliganded dimer mediated by its membrane proximal FNIII domains, and the invertebrate epidermal growth factor receptors (EGFRs) that form dimers of varying stability and poorly characterized structure. How ligand induces activation in these cases is not well understood and may involve conformational rearrangement in a dimer or formation of higher order oligomers (or both). We are using cryo-electron microscopy to gain structural insights into the ligand induced changes for these dimeric RTKs, and test our structure derived mechanistic hypotheses with biochemical, cellular and in vivo assays.
Understanding how the membrane environment directs RTK structure and function:
As part of a new NIH-funded interdisciplinary team science program, we and several other laboratories in the Departments of Pharmacology and Cell Biology are working to understand how membrane composition directs membrane protein structure and function. We seek to define the components (lipid & protein) of functional complexes isolated from native membranes, to study the role of the local membrane environment in the function and regulation of the integral membrane proteins, and to determine the 3-dimensional structures of functional complexes. Members of the team focus on different biological systems exploiting their complementary expertise in cryo-electron microscopy, mass spectrometry, multi-omic analysis, optical imaging, biochemistry and cellular signaling. In the Ferguson group, we focus on select RTKs where modulation of function by lipid components is well characterized, and the potential to alter receptor function with drugs that modulate the local membrane environment has been suggested.
Antibody modulation of RTK regulation
Our laboratory has a long-standing interest in the mechanisms of inhibition of receptor tyrosine kinases (RTKs) by therapeutic antibodies, most notably those that bind the epidermal growth factor receptor (EGFR) - one of the first targets of antibody-based drugs to treat cancer. Most therapeutic antibodies to EGFR family members were developed before there was any structural understanding of the activation mechanism of these receptors. Whereas most therapeutic EGFR antibodies block ligand binding, inhibition of EGFR activity contributes little to the clinical effects. We seek to understand how select existing antibodies may alter receptor conformation to modulate function and whether somatic mutations in EGFR receptors may alter antibody binding. We are also developing new mechanism-based antibody therapeutics, drawing on the rich understanding of EGFR family receptor structure and dynamics. We combine X-ray crystallography, cryoEM, biochemistry, computational analysis, and cellular studies to address these questions.
Medical Subject Headings (MeSH)
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Mark A Lemmon, PhD, FRS
Anatoly Kiyatkin, PhD
ErbB Receptors
Cell Membrane
Crystallography, X-Ray
Publications
2024
Structural insights into the role and targeting of EGFRvIII
Bagchi A, Stayrook S, Xenaki K, Starbird C, Doulkeridou S, El Khoulati R, Roovers R, Schmitz K, van Bergen En Henegouwen P, Ferguson K. Structural insights into the role and targeting of EGFRvIII. Structure 2024 PMID: 38908376, DOI: 10.1016/j.str.2024.05.018.Peer-Reviewed Original ResearchAltmetric
2022
Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias
Hu C, Leche CA, Kiyatkin A, Yu Z, Stayrook SE, Ferguson KM, Lemmon MA. Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias. Nature 2022, 602: 518-522. PMID: 35140400, PMCID: PMC8857055, DOI: 10.1038/s41586-021-04393-3.Peer-Reviewed Original ResearchCitationsAltmetric
2020
Insulin and epidermal growth factor receptor family members share parallel activation mechanisms
Ferguson KM, Hu C, Lemmon MA. Insulin and epidermal growth factor receptor family members share parallel activation mechanisms. Protein Science 2020, 29: 1331-1344. PMID: 32297376, PMCID: PMC7255510, DOI: 10.1002/pro.3871.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsCitationsMeSH Keywords and ConceptsConceptsReceptor tyrosine kinasesEpidermal growth factor receptorLigand-binding moduleInsulin receptorAutoinhibitory interactionsRecent cryo-electron microscopy structuresCryo-electron microscopy structureFirst receptor tyrosine kinasesRecent cryo-EM structureEGFR activation mechanismsEpidermal growth factor receptor family membersActivated insulin receptorIntramolecular autoinhibitory interactionCryo-EM structureActivation mechanismCysteine-rich domainFibronectin type III domainReceptor family membersEGFR family membersType III domainMicroscopy structureDomain compositionTransmembrane regionGrowth factor receptorLike domain
2018
Molecular basis for necitumumab inhibition of EGFR variants associated with acquired cetuximab resistance.
Bagchi A, Haidar JN, Eastman SW, Vieth M, Topper M, Iacolina MD, Walker JM, Forest A, Shen Y, Novosiadly RD, Ferguson KM. Molecular basis for necitumumab inhibition of EGFR variants associated with acquired cetuximab resistance. Molecular Cancer Therapeutics 2018, 17: molcanther.0575.2017. PMID: 29158469, PMCID: PMC5925748, DOI: 10.1158/1535-7163.mct-17-0575.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and Concepts
2017
EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics
Freed DM, Bessman NJ, Kiyatkin A, Salazar-Cavazos E, Byrne PO, Moore JO, Valley CC, Ferguson KM, Leahy DJ, Lidke DS, Lemmon MA. EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics. Cell 2017, 171: 683-695.e18. PMID: 28988771, PMCID: PMC5650921, DOI: 10.1016/j.cell.2017.09.017.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsReceptor tyrosine kinasesEpidermal growth factor receptorEGFR ligandsEGFR extracellular regionG protein-coupled receptorsDifferent EGFR ligandsCellular programsDifferent activating ligandsEGFR dimersCell signalingGrowth factor receptorExtracellular regionDimeric conformationEGFR dimerizationNew therapeutic opportunitiesReceptor dimersTyrosine kinaseBreast cancer cellsDimerization strengthActivating ligandsFactor receptorCancer cellsEpigenTherapeutic opportunitiesBiased agonismDimerization of Tie2 mediated by its membrane-proximal FNIII domains
Moore JO, Lemmon MA, Ferguson KM. Dimerization of Tie2 mediated by its membrane-proximal FNIII domains. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 4382-4387. PMID: 28396397, PMCID: PMC5410832, DOI: 10.1073/pnas.1617800114.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsExtracellular regionFNIII domainsResolution X-ray crystal structureMembrane-proximal fibronectin type III domainsDomain-mediated interactionsDifferent cellular contextsLigand-binding regionHigher-order oligomersTie2 activationFibronectin type III domainReceptor tyrosine kinasesTyrosine kinase familyEGF-homology domainThird FNIII domainType III domainPrevious structural studiesStructural studiesHomology domainCellular contextKinase familyDimer interfaceDimerization modeReceptor dimerizationTyrosine kinasePrimary activator
Academic Achievements and Community Involvement
activity Member
CommitteesScholar Awards CommitteeDetails09/01/2019 - 06/01/2022
Links & Media
News
- June 28, 2023Source: Yale West Campus
Yale Scientists Receive $10.5M for ‘Team Science’ Exploration of Membrane Proteins in Their Natural Environment
- March 30, 2022
The Growth of the Cancer Biology Institute
- February 08, 2022
‘Decision Switch’ Discovered in Mutations Linked to Common Brain Tumor
- January 31, 2021Source: Yale Daily News
Yale Postdoc Wins First Cell Press Rising Black Scientists Award
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