Prof Kenneth Linton
Professor of Protein Biochemistry
Blizard Institute
Faculty of Medicine and Dentistry, Queen Mary University of London
Faculty of Medicine and Dentistry, 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
Mazza T, Roumeliotis TI, Garitta E, Drew D, Rashid ST, Indiveri C, Choudhary JS, Linton KJ and Beis K (2024). Unveiling the Modulation of MRP2 Activity: Insights from Phosphorylation and Drug Interactions. Elsevier Biochimica et Biophysica Acta (BBA) - Bioenergetics vol. 1865, Mazza T, Roumeliotis TI, Garitta E, Drew D, Rashid ST, Indiveri C, Choudhary JS, Linton KJ and Beis K (2024). Structural basis for the modulation of MRP2 activity by phosphorylation and drugs. Springer Nature Nature Communications vol. 15, (1) Cheema Y, Linton KJ and Jabeen I (2024). Molecular Modeling Studies to Probe the Binding Hypothesis of Novel Lead Compounds against Multidrug Resistance Protein ABCB1. MDPI Biomolecules vol. 14, (1) 2023
Zöllner J, Finer S, Linton KJ, van Heel DA, Williamson C and Dixon PH (2023). Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom. Springer Nature Scientific Reports vol. 13, (1) Cheema Y, Kiani YS, Linton KJ and Jabeen I (2023). Identification and Empiric Evaluation of New Inhibitors of the Multidrug Transporter P-Glycoprotein (ABCB1). MDPI International Journal of Molecular Sciences vol. 24, (6) 2021
Sasitharan K, Iqbal HA, Bifsa F, Olszewska A and Linton KJ (2021). ABCB1 Does Not Require the Side-Chain Hydrogen-Bond Donors Gln347, Gln725, Gln990 to Confer Cellular Resistance to the Anticancer Drug Taxol. MDPI International Journal of Molecular Sciences vol. 22, (16) 2020
Emmanouilidi A, Casari I, Akkaya BG, Maffucci T, Furic L, Guffanti F, Broggini M, Chen X, Maxuitenko YY, Keeton AB, Piazza GA, Linton KJ and Falasca M (2020). Inhibition of the Lysophosphatidylinositol Transporter ABCC1 Reduces Prostate Cancer Cell Growth and Sensitizes to Chemotherapy. MDPI Cancers vol. 12, (8) Goodchild E, Stoetaert J, Drake W, Linton K and Brown MJ (2020). OR09-05 Expression of SLC35F1 in the Plasma Membrane of Cells of Aldosterone Producing Cell Clusters (APCCs) and Its Possible Role in Aldosterone Synthesis. The Endocrine Society Journal of the Endocrine Society vol. 4, (Supplement_1) or09-or05. 2019
Meyre D, Andress EJ, Sharma T, Snippe M, Asif H, Maharaj A, Vatin V, Gaget S, Besnard P, Choquet H, Froguel P and Linton KJ (2019). Contribution of rare coding mutations in CD36 to type 2 diabetes and cardio-metabolic complications. Springer Nature Scientific Reports vol. 9, (1) Adamska A, Domenichini A, Capone E, Damiani V, Akkaya BG, Linton KJ, Di Sebastiano P, Chen X, Keeton AB, Ramirez-Alcantara V, Maxuitenko Y, Piazza GA, De Laurenzi V, Sala G and Falasca M (2019). Pharmacological inhibition of ABCC3 slows tumour progression in animal models of pancreatic cancer. Springer Nature Journal of Experimental & Clinical Cancer Research vol. 38, (1) Adamska A, Ferro R, Lattanzio R, Capone E, Domenichini A, Damiani V, Chiorino G, Akkaya BG, Linton KJ, De Laurenzi V, Sala G and Falasca M (2019). ABCC3 is a novel target for the treatment of pancreatic cancer. Elsevier Advances in Biological Regulation vol. 73, 2018
Kawecki C, Bocquet O, Schmelzer CEH, Heinz A, Ihling C, Wahart A, Romier B, Bennasroune A, Blaise S, Terryn C, Linton KJ, Martiny L, Duca L and Maurice P (2018). Identification of CD36 as a new interaction partner of membrane NEU1: potential implication in the pro-atherogenic effects of the elastin receptor complex. Springer Nature Cellular and Molecular Life Sciences vol. 76, (4) 791-807. Rahman MM, Hazan A, Selway JL, Herath DS, Harwood CA, Pirzado MS, Atkar R, Kelsell DP, Linton KJ, Philpott MP and Neill GW (2018). A novel mechanism for activation of GLI1 by nuclear SMO that escapes anti-SMO inhibitors. American Association for Cancer Research (AACR) Cancer Research vol. 78, (10) 2017
Andress EJ, Nicolaou M, McGeoghan F and Linton KJ (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. Cell Mol Life Sci 2015
Linton KJ (2015). Lipid flopping in the liver. Portland Press Biochemical Society Transactions vol. 43, (5) 1003-1010. Akkaya BG, Zolnerciks JK, Ritchie TK, Bauer B, Hartz AMS, Sullivan JA and Linton KJ (2015). The multidrug resistance pump ABCB1 is a substrate for the ubiquitin ligase NEDD4-1. Taylor & Francis Molecular Membrane Biology vol. 32, (2) 39-45. 2014
Zolnerciks JK, Akkaya BG, Snippe M, Chiba P, Seelig A and Linton KJ (2014). The Q loops of the human multidrug resistance transporter ABCB1 are necessary to couple drug binding to the ATP catalytic cycle. FASEB J vol. 28, (10) 4335-4346. Andress EJ, Nicolaou M, Romero MR, Naik S, Dixon PH, Williamson C and Linton KJ (2014). A molecular mechanistic explanation for the spectrum of cholestatic disease caused by the S320F variant of ABCB4. Wiley Online Hepatology Janha RE, Worwui A, Linton KJ, Shaheen SO, Sisay-Joof F and Walton RT (2014). Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution. BMC Evol Biol vol. 14, Sanders D, Zampronio CG, Nettleship JE, Owens RJ, Owen C and Linton KJ (2014). Characterisation of the scavenger receptor CD36. BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE vol. 92, (6) 587-587. 2013
Blaydon DC, Lind LK, Plagnol V, Linton KJ, Smith FJD, Wilson NJ, McLean WHI, Munro CS, South AP, Leigh IM, O'Toole EA, Lundström A and Kelsell DP (2013). Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma. Am J Hum Genet vol. 93, (2) 330-335. 2012
Falasca M and Linton KJ (2012). Investigational ABC transporter inhibitors. Expert Opin Investig Drugs vol. 21, (5) 657-666. Nicolaou M, Andress EJ, Zolnerciks JK, Dixon PH, Williamson C and Linton KJ (2012). Canalicular ABC transporters and liver disease. J Pathol vol. 226, (2) 300-315. 2011
Groen A, Romero MR, Kunne C, Hoosdally SJ, Dixon PH, Wooding C, Williamson C, Seppen J, Van den Oever K, Mok KS, Paulusma CC, Linton KJ and Oude Elferink RPJ (2011). Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity. Gastroenterology vol. 141, (5) Zolnerciks JK, Andress EJ, Nicolaou M and Linton KJ (2011). Structure of ABC transporters. Essays Biochem vol. 50, (1) 43-61. Linton KJ, Zolnerciks JK and Schmitt L (2011). General Introduction, Structure and Likely Mechanism of Action of ABC Transport Proteins. The ABC Transporters of Human Physiology and Disease: Genetics and Biochemistry of ATP Binding Cassette Transporters , Editors: Linton KJ and Holland IB. World Scientific Publishing Linton KJ and Holland IB (2011). The ABC transporters of human physiology and disease: Genetics and biochemistry of atp binding cassette transporters. 2009
Hoosdally SJ, Andress EJ, Wooding C, Martin CA and Linton KJ (2009). The Human Scavenger Receptor CD36 GLYCOSYLATION STATUS AND ITS ROLE IN TRAFFICKING AND FUNCTION. J BIOL CHEM vol. 284, (24) 16277-16288. Dixon PH, van Mil SWC, Chambers J, Strautnieks S, Thompson RJ, Lammert F, Kubitz R, Keitel V, Glantz A, Mattsson LA, Marschall HU, Molokhia M, Moore GE, Linton KJ and Williamson C (2009). Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. GUT vol. 58, (4) 537-544. Byrne JA, Strautnieks SS, Ihrke G, Pagani F, Kinsely AS, Linton KJ, Mieli-Vergani G and Thompson RJ (2009). Missense Mutations and Single Nucleotide Polymorphisms in ABCB11 Impair Bile Salt Export Pump Processing and Function or Disrupt Pre-Messenger RNA Splicing. HEPATOLOGY vol. 49, (2) 553-567. 2007
Zolnerciks JK, Wooding C and Linton KJ (2007). Evidence for a Sav1866-like architecture for the human multidrug transporter P-glycoprotein. FASEB J vol. 21, (14) 3937-3948. Martin CA, Longman E, Wooding C, Hoosdally SJ, Ali S, Aitman TJ, Gutmann DAP, Freemont PS, Byrne B and Linton KJ (2007). Cd36, a class B scavenger receptor, functions as a monomer to bind acetylated and oxidized low-density lipoproteins. PROTEIN SCI vol. 16, (11) 2531-2541. Linton KJ (2007). Structure and function of ABC transporters. PHYSIOLOGY vol. 22, 122-130. Linton KJ and Higgins CF (2007). Structure and function of ABC transporters: the ATP switch provides flexible control. PFLUG ARCH EUR J PHY vol. 453, (5) 555-567. 2005
Elliott JI, Surprenant A, Marelli-Berg FM, Cooper JC, Cassady-Cain RL, Wooding C, Linton KJ, Alexander DR and Higgins CF (2005). Membrane phosphatidylserine distribution as a non-apoptotic signalling mechanism in lymphocytes. Nat. Cell Biol. vol. 7, 808-816. 2004
Lepretre F, Linton KJ, Lacquemant C, Vatin V, Samson C, Dina C, Chikri M, Ali S, Scherer P, Seron K, Vasseur F, Aitman T and Froguel P (2004). Genetic study of the CD36 gene In a French diabetic population. DIABETES METAB vol. 30, (5) 459-463. Higgins CF and Linton KJ (2004). The ATP switch model for ABC transporters. NAT STRUCT MOL BIOL vol. 11, (10) 918-926. Rothnie A, Storm J, Campbell J, Linton KJ, Kerr ID and Callaghan R (2004). The topography of transmembrane segment six is altered during the catalytic cycle of P-glycoprotein. J BIOL CHEM vol. 279, (33) 34913-34921. Lepretre F, Vasseur F, Vaxillaire M, Scherer PE, Ali S, Linton KJ, Aitman T and Froguel P (2004). A CD36 nonsense mutation associated with insulin resistance and familial type 2 diabetes. Hum Mutat vol. 24, 104-110. 2003
Kerr ID, Berridge G, Linton KJ, Higgins CF and Callaghan R (2003). Definition of the domain boundaries is critical to the expression of the nucleotide-binding domains of P-glycoprotein. EUR BIOPHYS J BIOPHY vol. 32, (7) 644-654. Jodoin J, Demeule M, Fenart L, Cecchelli R, Farmer S, Linton KJ, Higgins CF and Beliveau R (2003). P-glycoprotein in blood-brain barrier endothelial cells: interaction and oligomerization with caveolins. J NEUROCHEM vol. 87, (4) 1010-1023. Stenham DR, Campbell JD, Sansom MSP, Higgins CF, Kerr ID and Linton KJ (2003). An atomic detail model for the human ATP binding cassette transporter P-glycoprotein derived from disulphide cross-linking and homology modeling. FASEB J vol. 17, (13) 2287-+. Gabriel MP, Storm J, Rothnie A, Taylor AM, Linton KJ, Kerr ID and Callaghan R (2003). Communication between the nucleotide binding domains of P-glycoprotein occurs via conformational changes that involve residue 508. BIOCHEMISTRY-US vol. 42, (25) 7780-7789. Mullenbach R, Linton KJ, Wiltshire S, Weerasekera N, Chambers J, Elias E, Higgins CF, Johnston DG, McCarthy MI and Williamson C (2003). ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy. J MED GENET vol. 40, (5) Byrne JA, Strautniks SS, Higgins CF, Linton KJ and Thompson RJ (2003). Function of BSEP., Editors: Paumgartner G. Springer Linton KJ, Rosenberg MF, Kerr ID and Higgins CF (2003). Chapter 4 Structure of ABC Transporters. ABC Proteins Elsevier 2002
Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ and Thompson RJ (2002). The human bile salt export pump: Characterization of substrate specificity and identification of inhibitors. GASTROENTEROLOGY vol. 123, (5) 1649-1658. Linton KJ and Higgins CF (2002). P-glycoprotein misfolds in Escherichia coli: evidence against alternating-topology models of the transport cycle. MOL MEMBR BIOL vol. 19, (1) 51-58. Linton KJ, Rosenberg M, Kerr ID and Higgins CF (2002). Structure of ABC transporters. ABC Proteins , Editors: Holland IB, Cole SPC, Kuchler K and Higgins CF. Academic Press Higgins CF and Linton KJ (2002). ABC transporters: An introduction and overview. ABC Proteins , Editors: Holland IB, Cole SPC, Kuchler K and Higgins CF. Academic Press 2001
Taylor AM, Storm J, Soceneantu L, Linton KJ, Gabriel M, Martin C, Woodhouse J, Blott E, Higgins CF and Callaghan R (2001). Detailed characterization of cysteine-less P-glycoprotein reveals subtle pharmacological differences in function from wild-type protein. BRIT J PHARMACOL vol. 134, (8) 1609-1618. Rosenberg MF, Velarde G, Ford RC, Martin C, Berridge G, Kerr ID, Callaghan R, Schmidlin A, Wooding C, Linton KJ and Higgins CF (2001). Repacking of the transmembrane domains of P-glycoprotein during the transport ATPase cycle. EMBO J vol. 20, (20) 5615-5625. Higgins CF and Linton KJ (2001). The xyz of ABC transporters. Science vol. 293, (5536) 1782-1784. Higgins CF and Linton KJ (2001). Structural biology - The xyz of ABC transporters. SCIENCE vol. 293, (5536) 1782-1784. 2000
Dixon PH, Weerasekera N, Linton KJ, Donaldson O, Chambers J, Egginton E, Weaver J, Nelson-Piercy C, de Swiet M, Warnes G, Elias E, Higgins CF, Johnston DG, McCarthy MI and Williamson C (2000). Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. HUM MOL GENET vol. 9, (8) 1209-1217. 1999
Blott EJ, Higgins CF and Linton KJ (1999). Cysteine-scanning mutagenesis provides no evidence for the extracellular accessibility of the nucleotide-binding domains of the multidrug resistance transporter P-glycoprotein. EMBO J vol. 18, (23) 6800-6808. Higgins CF, Weylandt KH, Nastrucci C, Sardini A, Linton K, Diaz M and Valverde MA (1999). Cell swelling-activated chloride channels and their regulation by P-glycoprotein. Chloride Channels , Editors: Kozlowski R. Isis Press 1998
Linton KJ and Higgins CF (1998). The Escherichia coli ATP-binding cassette (ABC) proteins. MOL MICROBIOL vol. 28, (1) 5-13. 1997
Higgins CF, Callaghan R, Linton KJ, Rosenberg MF and Ford RC (1997). Structure of the multidrug resistance P-glycoprotein. SEMIN CANCER BIOL vol. 8, (3) 135-142. 1995
LINTON KJ, JARVIS BW and HUTCHINSON CR (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-ERYTHRAEA. GENE vol. 153, (1) 33-40. 1994
LINTON KJ, COOPER HN, HUNTER IS and LEADLAY PF (1994). AN ABC-TRANSPORTER FROM STREPTOMYCES-LONGISPOROFLAVUS CONFERS RESISTANCE TO THE POLYETHER-IONOPHORE ANTIBIOTIC TETRONASIN. MOL MICROBIOL vol. 11, (4) 777-785. 1988
LINTON KJ and HUNTER IS (1988). CLONING OF DNA-SEQUENCES FROM STREPTOMYCES-LONGISPOROFLAVUS WHICH CONFER INCREASED RESISTANCE TO THE IONOPHORE ANTIBIOTIC TETRONASIN IN STREPTOMYCES-LIVIDANS. HEREDITY vol. 61, 304-305. Grants
Development 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)