Prof Kenneth Linton
Professor of Protein Biochemistry
Blizard Institute
Queen Mary University of London
Queen Mary University of London
Research
human liver model, bile formation and flow, cholestasis, iPSC, hepatocyte plate, ABC transporters
Interests
Bile formation and flow from the liver across the canalicular membrane and into the biliary tree is necessary for dietary fat absorption from the gut. It is also a major pathway for elimination of toxins and metabolic waste products. ATP Binding Cassette transporters are key to bile flow from the liver hepatocytes. Mutations in these transporters cause cholestasis and a range of secondary pathologies, from gallstones to liver failure in childhood. They are also common off-targets of therapeutic drugs, a major cause of failure of drugs in the pipeline due to the inadequacy of animal models to replicate the human drug-induced liver injury.Recently, it has become important to study these transporters as a system in a relevant cell-type. We have therefore developed a differentiation protocol for human hepatocytes from induced-pluripotent stem cells. The cellular ultrastructure of these induced-hepatocytes (iHEPs) is similar to liver and they produce albumin and express CYP3A4 important for xenobiotic detoxification. Importantly, the iHEPs make and transport bile into canaliculi formed between cells. We can also mimic cholestasis by application of known cholestatic drugs or by feeding excess bile acids. RNAseq analyses has identified the early markers of inflammation generated by the iHEPs in response to cholestasis and also the adaptive pathways triggered in response (manuscripts in preparation).
We aim to use these human iHEPs to model human disease and to develop an accurate test bed for drugs that cause drug-induced liver injury. The first description of the model’s utility is described in Mazza et al Nat Comms 2024 where it was used to demonstrate the control of MRP2 (ABCC2) function by phosphorylation.
Publications
2024
Unveiling the Modulation of MRP2 Activity: Insights from Phosphorylation and Drug InteractionsMazza T, Roumeliotis TI, Garitta E, Drew D, Rashid ST, Indiveri C, Choudhary JS, Linton KJ et al.
Biochimica Et Biophysica Acta (Bba) - Bioenergetics, Elsevier vol. 1865
01-09-2024
Structural basis for the modulation of MRP2 activity by phosphorylation and drugsMazza T, Roumeliotis TI, Garitta E, Drew D, Rashid ST, Indiveri C, Choudhary JS, Linton KJ et al.
Nature Communications, Springer Nature vol. 15 (1)
04-03-2024
Molecular Modeling Studies to Probe the Binding Hypothesis of Novel Lead Compounds against Multidrug Resistance Protein ABCB1Cheema Y, Linton KJ, Jabeen I
Biomolecules, Mdpi vol. 14 (1)
16-01-2024
2023
Rare variant contribution to cholestatic liver disease in a South Asian population in the United KingdomZöllner J, Finer S, Linton KJ, van Heel DA, Williamson C, Dixon PH
Scientific Reports, Springer Nature vol. 13 (1)
19-05-2023
Identification and Empiric Evaluation of New Inhibitors of the Multidrug Transporter P-Glycoprotein (ABCB1)Cheema Y, Kiani YS, Linton KJ, Jabeen I
International Journal of Molecular Sciences, Mdpi vol. 24 (6)
10-03-2023
2021
ABCB1 Does Not Require the Side-Chain Hydrogen-Bond Donors Gln347, Gln725, Gln990 to Confer Cellular Resistance to the Anticancer Drug TaxolSasitharan K, Iqbal HA, Bifsa F, Olszewska A, Linton KJ
International Journal of Molecular Sciences, Mdpi vol. 22 (16)
09-08-2021
2020
Inhibition of the Lysophosphatidylinositol Transporter ABCC1 Reduces Prostate Cancer Cell Growth and Sensitizes to ChemotherapyEmmanouilidi A, Casari I, Akkaya BG, Maffucci T, Furic L, Guffanti F, Broggini M, Chen X et al.
Cancers, Mdpi vol. 12 (8)
23-07-2020
OR09-05 Expression of SLC35F1 in the Plasma Membrane of Cells of Aldosterone Producing Cell Clusters (APCCs) and Its Possible Role in Aldosterone SynthesisGoodchild E, Stoetaert J, Drake W, Linton K, Brown MJ
Journal of The Endocrine Society, The Endocrine Society vol. 4 (Supplement_1), or09-or05.
08-05-2020
2019
Contribution of rare coding mutations in CD36 to type 2 diabetes and cardio-metabolic complicationsMeyre D, Andress EJ, Sharma T, Snippe M, Asif H, Maharaj A, Vatin V, Gaget S et al.
Scientific Reports, Springer Nature vol. 9 (1)
20-11-2019
Pharmacological inhibition of ABCC3 slows tumour progression in animal models of pancreatic cancerAdamska A, Domenichini A, Capone E, Damiani V, Akkaya BG, Linton KJ, Di Sebastiano P, Chen X et al.
Journal of Experimental & Clinical Cancer Research, Springer Nature vol. 38 (1)
05-08-2019
ABCC3 is a novel target for the treatment of pancreatic cancerAdamska A, Ferro R, Lattanzio R, Capone E, Domenichini A, Damiani V, Chiorino G, Akkaya BG et al.
Advances in Biological Regulation, Elsevier vol. 73
24-04-2019
2018
Identification of CD36 as a new interaction partner of membrane NEU1: potential implication in the pro-atherogenic effects of the elastin receptor complexKawecki C, Bocquet O, Schmelzer CEH, Heinz A, Ihling C, Wahart A, Romier B, Bennasroune A et al.
Cellular and Molecular Life Sciences, Springer Nature vol. 76 (4), 791-807.
29-11-2018
A novel mechanism for activation of GLI1 by nuclear SMO that escapes anti-SMO inhibitorsRahman MM, Hazan A, Selway JL, Herath DS, Harwood CA, Pirzado MS, Atkar R, Kelsell DP et al.
Cancer Research, American Association For Cancer Research (Aacr) vol. 78 (10)
14-05-2018
2017
ABCB4 missense mutations D243A, K435T, G535D, I490T, R545C, and S978P significantly impair the lipid floppase and likely predispose to secondary pathologies in the human population.Andress EJ, Nicolaou M, McGeoghan F, Linton KJ
Cell Mol Life Sci
20-02-2017
2015
Lipid flopping in the liver.Linton KJ
Biochemical Society Transactions, Portland Press vol. 43 (5), 1003-1010.
01-10-2015
The multidrug resistance pump ABCB1 is a substrate for the ubiquitin ligase NEDD4-1Akkaya BG, Zolnerciks JK, Ritchie TK, Bauer B, Hartz AMS, Sullivan JA, Linton KJ
Molecular Membrane Biology, Taylor & Francis vol. 32 (2), 39-45.
17-02-2015
2014
The Q loops of the human multidrug resistance transporter ABCB1 are necessary to couple drug binding to the ATP catalytic cycle.Zolnerciks JK, Akkaya BG, Snippe M, Chiba P, Seelig A, Linton KJ
Faseb J vol. 28 (10), 4335-4346.
01-10-2014
A molecular mechanistic explanation for the spectrum of cholestatic disease caused by the S320F variant of ABCB4Andress EJ, Nicolaou M, Romero MR, Naik S, Dixon PH, Williamson C, Linton KJ
Hepatology, Wiley Online
01-04-2014
Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution.Janha RE, Worwui A, Linton KJ, Shaheen SO, Sisay-Joof F, Walton RT
Bmc Evol Biol vol. 14
01-04-2014
Characterisation of the scavenger receptor CD36Sanders D, Zampronio CG, Nettleship JE, Owens RJ, Owen C, Linton KJ
Biochemistry and Cell Biology-Biochimie Et Biologie Cellulaire vol. 92 (6), 587-587.
01-01-2014
2013
Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma.Blaydon DC, Lind LK, Plagnol V, Linton KJ, Smith FJD, Wilson NJ, McLean WHI, Munro CS et al.
Am J Hum Genet vol. 93 (2), 330-335.
08-08-2013
Aquaporin 5 (AQP5), a water channel protein, is mutated in autosomal dominant diffuse non-epidermolytic palmoplantar keratodermaBlaydon DC, Lind L, Plagnol V, Linton KJ, South AP, Leigh IM, O'Toole EA, Lundstrom A et al.
01-01-2013
2012
Investigational ABC transporter inhibitors.Falasca M, Linton KJ
Expert Opin Investig Drugs vol. 21 (5), 657-666.
01-05-2012
Canalicular ABC transporters and liver disease.Nicolaou M, Andress EJ, Zolnerciks JK, Dixon PH, Williamson C, Linton KJ
J Pathol vol. 226 (2), 300-315.
01-01-2012
2011
Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity.Groen A, Romero MR, Kunne C, Hoosdally SJ, Dixon PH, Wooding C, Williamson C, Seppen J et al.
Gastroenterology vol. 141 (5)
01-11-2011
Structure of ABC transporters.Zolnerciks JK, Andress EJ, Nicolaou M, Linton KJ
Essays Biochem vol. 50 (1), 43-61.
07-09-2011
General Introduction, Structure and Likely Mechanism of Action of ABC Transport ProteinsLinton KJ, Zolnerciks JK, Schmitt L, Linton KJ, Holland IB
In The Abc Transporters of Human Physiology and Disease: Genetics and Biochemistry of Atp Binding Cassette Transporters, World Scientific Publishing 1-27.
01-09-2011
The ABC transporters of human physiology and disease: Genetics and biochemistry of atp binding cassette transportersLinton KJ, Holland IB
01-01-2011
2009
The Human Scavenger Receptor CD36 GLYCOSYLATION STATUS AND ITS ROLE IN TRAFFICKING AND FUNCTIONHoosdally SJ, Andress EJ, Wooding C, Martin CA, Linton KJ
J Biol Chem vol. 284 (24), 16277-16288.
12-06-2009
Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancyDixon PH, van Mil SWC, Chambers J, Strautnieks S, Thompson RJ, Lammert F, Kubitz R, Keitel V et al.
Gut vol. 58 (4), 537-544.
01-04-2009
Missense Mutations and Single Nucleotide Polymorphisms in ABCB11 Impair Bile Salt Export Pump Processing and Function or Disrupt Pre-Messenger RNA SplicingByrne JA, Strautnieks SS, Ihrke G, Pagani F, Kinsely AS, Linton KJ, Mieli-Vergani G, Thompson RJ
Hepatology vol. 49 (2), 553-567.
01-02-2009
2007
Evidence for a Sav1866-like architecture for the human multidrug transporter P-glycoproteinZolnerciks JK, Wooding C, Linton KJ
Faseb J vol. 21 (14), 3937-3948.
01-12-2007
Cd36, a class B scavenger receptor, functions as a monomer to bind acetylated and oxidized low-density lipoproteinsMartin CA, Longman E, Wooding C, Hoosdally SJ, Ali S, Aitman TJ, Gutmann DAP, Freemont PS et al.
Protein Sci vol. 16 (11), 2531-2541.
01-11-2007
Structure and function of ABC transportersLinton KJ
Physiology vol. 22, 122-130.
01-04-2007
Structure and function of ABC transporters: the ATP switch provides flexible controlLinton KJ, Higgins CF
Pflug Arch Eur J Phy vol. 453 (5), 555-567.
01-02-2007
2005
Investigation of MRNA splicing associated with the common BSEP mutations: An important disease mechanism for D482Byrne JA, Strautnieks SS, Ihrke G, Knisley AS, Jankowska I, Pawlowska J, Linton KJ, Higgins CF et al.
01-10-2005
Membrane phosphatidylserine distribution as a non-apoptotic signalling mechanism in lymphocytesElliott JI, Surprenant A, Marelli-Berg FM, Cooper JC, Cassady-Cain RL, Wooding C, Linton KJ, Alexander DR et al.
Nat. Cell Biol. vol. 7, 808-816.
01-01-2005
2004
Genetic study of the CD36 gene In a French diabetic populationLepretre F, Linton KJ, Lacquemant C, Vatin V, Samson C, Dina C, Chikri M, Ali S et al.
Diabetes Metab vol. 30 (5), 459-463.
01-11-2004
The ATP switch model for ABC transportersHiggins CF, Linton KJ
Nat Struct Mol Biol vol. 11 (10), 918-926.
01-10-2004
The topography of transmembrane segment six is altered during the catalytic cycle of P-glycoproteinRothnie A, Storm J, Campbell J, Linton KJ, Kerr ID, Callaghan R
J Biol Chem vol. 279 (33), 34913-34921.
13-08-2004
A CD36 nonsense mutation associated with insulin resistance and familial type 2 diabetesLepretre F, Vasseur F, Vaxillaire M, Scherer PE, Ali S, Linton KJ, Aitman T, Froguel P
Hum Mutat vol. 24, 104-110.
01-01-2004
2003
Definition of the domain boundaries is critical to the expression of the nucleotide-binding domains of P-glycoproteinKerr ID, Berridge G, Linton KJ, Higgins CF, Callaghan R
Eur Biophys J Biophy vol. 32 (7), 644-654.
01-11-2003
P-glycoprotein in blood-brain barrier endothelial cells: interaction and oligomerization with caveolinsJodoin J, Demeule M, Fenart L, Cecchelli R, Farmer S, Linton KJ, Higgins CF, Beliveau R
J Neurochem vol. 87 (4), 1010-1023.
01-11-2003
An atomic detail model for the human ATP binding cassette transporter P-glycoprotein derived from disulphide cross-linking and homology modelingStenham DR, Campbell JD, Sansom MSP, Higgins CF, Kerr ID, Linton KJ
Faseb J vol. 17 (13), 2287-+.
01-10-2003
Communication between the nucleotide binding domains of P-glycoprotein occurs via conformational changes that involve residue 508Gabriel MP, Storm J, Rothnie A, Taylor AM, Linton KJ, Kerr ID, Callaghan R
Biochemistry-Us vol. 42 (25), 7780-7789.
01-07-2003
ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancyMullenbach R, Linton KJ, Wiltshire S, Weerasekera N, Chambers J, Elias E, Higgins CF, Johnston DG et al.
J Med Genet vol. 40 (5)
01-05-2003
Characterisation of substrate specificity and identification of inhibitors of the human bile salt export pump, BSEPByrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ
01-05-2003
ABCB4 sequence variation in women with intrahepatic cholestasis of pregnancyMullenbach R, Linton KJ, Wiltshire S, Elias E, McCarthy MI, Williamson C
01-04-2003
Function of BSEPByrne JA, Strautnieks SS, Higgins CF, Linton KJ, Thompson RJ, Paumgartner G, Keppler D, Leuschner U et al.
01-01-2003
Function of BSEP.Byrne JA, Strautniks SS, Higgins CF, Linton KJ, Thompson RJ, Paumgartner G
01-01-2003
Chapter 4 Structure of ABC TransportersLinton KJ, Rosenberg MF, Kerr ID, Higgins CF
In Abc Proteins, Elsevier 65-80.
01-01-2003
2002
The human bile salt export pump: Characterization of substrate specificity and identification of inhibitorsByrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ
Gastroenterology vol. 123 (5), 1649-1658.
01-11-2002
In vitro characterisation of the human bile salt export pump, BSEP.Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ
01-10-2002
P-glycoprotein misfolds in Escherichia coli: evidence against alternating-topology models of the transport cycleLinton KJ, Higgins CF
Mol Membr Biol vol. 19 (1), 51-58.
01-01-2002
Structure of ABC transportersLinton KJ, Rosenberg M, Kerr ID, Higgins CF, Holland IB, Cole SPC, Kuchler K, Higgins CF
In Abc Proteins, Academic Press
01-01-2002
ABC transporters: An introduction and overviewHiggins CF, Linton KJ, Holland IB, Cole SPC, Kuchler K, Higgins CF
In Abc Proteins, Academic Press
01-01-2002
2001
Detailed characterization of cysteine-less P-glycoprotein reveals subtle pharmacological differences in function from wild-type proteinTaylor AM, Storm J, Soceneantu L, Linton KJ, Gabriel M, Martin C, Woodhouse J, Blott E et al.
Brit J Pharmacol vol. 134 (8), 1609-1618.
01-12-2001
Repacking of the transmembrane domains of P-glycoprotein during the transport ATPase cycleRosenberg MF, Velarde G, Ford RC, Martin C, Berridge G, Kerr ID, Callaghan R, Schmidlin A et al.
Embo J vol. 20 (20), 5615-5625.
15-10-2001
The xyz of ABC transportersHiggins CF, Linton KJ
Science vol. 293 (5536), 1782-1784.
07-09-2001
Structural biology - The xyz of ABC transportersHiggins CF, Linton KJ
Science vol. 293 (5536), 1782-1784.
07-09-2001
Structure and function of the multidrug resistance P-glycoproteinHiggins CF, Callaghan R, Linton K, Ford R, Rosenberg M
01-09-2001
2000
Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein traffickingDixon PH, Weerasekera N, Linton KJ, Donaldson O, Chambers J, Egginton E, Weaver J, Nelson-Piercy C et al.
Hum Mol Genet vol. 9 (8), 1209-1217.
01-05-2000
1999
Cysteine-scanning mutagenesis provides no evidence for the extracellular accessibility of the nucleotide-binding domains of the multidrug resistance transporter P-glycoproteinBlott EJ, Higgins CF, Linton KJ
Embo J vol. 18 (23), 6800-6808.
01-12-1999
Cell swelling-activated chloride channels and their regulation by P-glycoproteinHiggins CF, Weylandt KH, Nastrucci C, Sardini A, Linton K, Diaz M, Valverde MA, Kozlowski R
In Chloride Channels, Isis Press
01-01-1999
1998
The Escherichia coli ATP-binding cassette (ABC) proteinsLinton KJ, Higgins CF
Mol Microbiol vol. 28 (1), 5-13.
01-04-1998
1997
Evidence for a novel mechanism of resistance to the polyether polyketide tetronasin.Lewis HD, Floriano B, Linton KJ, White J, Bibb MJ, Hunter IS, Leadlay PF
31-07-1997
Structure of the multidrug resistance P-glycoproteinHiggins CF, Callaghan R, Linton KJ, Rosenberg MF, Ford RC
Semin Cancer Biol vol. 8 (3), 135-142.
01-06-1997
1995
CLONING OF THE GENES ENCODING THYMIDINE DIPHOSPHOGLUCOSE 4,6-DEHYDRATASE AND THYMIDINE DIPHOSPHO-4-KETO-6-DEOXYGLUCOSE 3,5-EPIMERASE FROM THE ERYTHROMYCIN-PRODUCING SACCHAROPOLYSPORA-ERYTHRAEALINTON KJ, JARVIS BW, HUTCHINSON CR
Gene vol. 153 (1), 33-40.
03-02-1995
1994
The impact of molecular genetics on understanding antibiotic biosynthesis: Design of new drugsLINTON KJ, THAMCHAIPENET A, HUNTER IS
01-05-1994
AN ABC-TRANSPORTER FROM STREPTOMYCES-LONGISPOROFLAVUS CONFERS RESISTANCE TO THE POLYETHER-IONOPHORE ANTIBIOTIC TETRONASINLINTON KJ, COOPER HN, HUNTER IS, LEADLAY PF
Mol Microbiol vol. 11 (4), 777-785.
01-02-1994
1988
CLONING OF DNA-SEQUENCES FROM STREPTOMYCES-LONGISPOROFLAVUS WHICH CONFER INCREASED RESISTANCE TO THE IONOPHORE ANTIBIOTIC TETRONASIN IN STREPTOMYCES-LIVIDANSLINTON KJ, HUNTER IS
Heredity vol. 61, 304-305.
01-10-1988
A Genes & Health pilot recall study of intrahepatic cholestasis of pregnancy and cholestatic liver diseaseConstantinides M, Gafton J, Garcia ACA, Genes and Health, Dixon PH, Williamson C, Linton K, Finer S et al.
In Medrxiv
ABCB1 Does Not Require the Side-Chain Hydrogen-Bond Donors Q347, Q725, Q990 to Confer Cellular Resistance to the Anticancer Drug TaxolSasitharan K, Iqbal HA, Bifsa F, Olszewska A, Linton KJ
In Preprints.Org
Rare variant contribution to cholestatic liver disease in a South Asian population in the United KingdomZöllner J, Finer S, Linton KJ, Team GAHR, van Heel DA, Williamson C, Dixon PH
In Medrxiv
Grants
Grants of specific relevance to Predictive in vitro ModelsDevelopment of a synthetic human iHEP culture system for DILI toxicology screeningKenneth Linton
£24,732 Animal Free Research UK
01-03-2024 - 28-02-2026
Modelling hepatic bile formation and flow in vitro to understand the damage associate molecular patterns resulting from cholestasis that predispose to liver diseaseKenneth Linton
£17,600 AZ AstraZeneca UK Limited
28-09-2020 - 27-09-2024
Lipid transfer between ABCA1 and apoA-1Kenneth Linton
£3,600 Great Britain Sasakawa Foundation
01-08-2020 - 31-07-2021
Targeting cancer cells with CD95R coated nanoparticlesKenneth Linton
£118,927 MRC Medical Research Council
01-10-2014 - 30-09-2018