Dr Kathryn Taylor

Principal Research Fellow

School of Pharmacy and Pharmaceutical Sciences

Overview

My main focus is the discovery of zinc signalling mechanisms both in health and disesase states. I have a particular focus on the role of zinc in cancer but not exclusively. I am also especially interested in the SLC39A family of zinc transporters, with focus on the members of the LIV-1 sub family.

We were the first to discover the LIV-1 sub family of zinc transporters due to the unique consensus motif that they contain.

We were the first to discover that zinc transporters require phosphorylation by a kinase to activate them to be able to transport zinc. We demonstarted this in ZIP7, the main zinc transporter that releases zinc into cells from cellualr stores, which required phosphorylation by CK2 kinase in order to be able to transport the zinc and release it from stores. This discovery enabled generation of a unique antibody that only recognises ZIP7 in its active zinc-transporting state. We are examining the use of this antibody to recognise cancers that are either becoming resistant to therapy or beginning to grow with more vigour.

We were the first to discover the mechanism of how zinc is essential for cell division. Zinc needs to enter into a cell through specific zinc transporters before the cell can begin to divide. Using a specific antibody to this molecule we can now prevent this cell division and are examining how this may be a usueful cancer treatment. Current animal trials have confirmed the ability of this antibody to effectively inhibit tumour growth, a quality that is observed in multiple cancer types, including those that are currently difiicult or impossible to treat.

Qualifications

BSc (Honours) in Physiology and Biochemistry, Reading University, 1974
PhD from Kings' College Hospital, London University in kidney preservation 1982

Relevant websites

Breast Cancer (Molecular Pharmacology) Group
Zinc-UK - an Association for scientists actively engaged in researching zinc in biology in the UK and Europe.
International Society for Zinc Biology - https://iszb.org/ - The main international society bringing together scientists from a diversity of fields with a common interest in the structural, biochemical, genetic and physiological aspects of zinc biology

Funding bodies that have supported my research

Breast Cancer Campaign
Wellcome Trust
Tenovus Cancer Care - https://www.tenovuscancercare.org.uk/
Life Sciences Research Network Wales - http://www.lsrnw.ac.uk/

Date
Type

2023

Farr, G., Jones, S. and Taylor, K. M. 2023. Methods to visualise zinc transporter proteins of the SLC39A family in cells [Chapter 4]. In: Hu, J. ed. Methods in Enzymology., Vol. 687. Elsevier, pp. 67-85., (10.1016/bs.mie.2023.04.020)
Taylor, K. M. 2023. The liv-1 subfamily of zinc transporters: from origins to present day discoveries. International Journal of Molecular Sciences 24(2), article number: 1255. (10.3390/ijms24021255)

2022

Jones, S., Farr, G., Nimmanon, T., Ziliotto, S., Gee, J. M. and Taylor, K. M. 2022. The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer. Exploration of Targeted Anti-tumor Therapy 3, pp. 224-239. (10.37349/etat.2022.00080)

2021

Kambe, T., Taylor, K. M. and Fu, D. 2021. Zinc transporters and their functional integration in mammalian cells. Journal of Biological Chemistry 296, article number: 100320. (10.1016/j.jbc.2021.100320)

2020

Nimmanon, T. et al. 2020. The ZIP6/ZIP10 heteromer is essential for the zinc-mediated trigger of mitosis. Cellular and Molecular Life Sciences 78, pp. 1781-1798. (10.1007/s00018-020-03616-6)
Suzuki, E. et al. 2020. Detailed analyses of the crucial functions of Zn transporter proteins in alkaline phosphatase activation. Journal of Biological Chemistry 295, pp. 5669-5684. (10.1074/jbc.RA120.012610)

2019

Nimmanon, T. and Taylor, K. M. 2019. Post-translational mechanisms of zinc signalling in cancer. In: Fukada, T. and Kambe, T. eds. Zinc Signaling. Springer, Singapore, pp. 319-345., (10.1007/978-981-15-0557-7_16)
Ziliotto, S., Gee, J. M. W., Ellis, I. O., Green, A. R., Finlay, P., Gobbato, A. and Taylor, K. M. 2019. Activated zinc transporter ZIP7 as an indicator of anti-hormone resistance in breast cancer. Metallomics 11(9), pp. 1579-1592. (10.1039/C9MT00136K)
Mero, M., Asraf, H., Sekler, I., Taylor, K. M. and Hershfinkel, M. 2019. ZnR/GPR39 upregulation of K+/Cl−-cotransporter 3 in tamoxifen resistant breast cancer cells. Cell Calcium 81, pp. 12-20. (10.1016/j.ceca.2019.05.005)
Ollig, J., Kloubert, V., Taylor, K. and Rink, L. 2019. B cell activation and proliferation increase intracellular zinc levels. Journal of Nutritional Biochemistry 64, pp. 72-79. (10.1016/j.jnutbio.2018.10.008)

2018

Ventura-Bixenshpaner, H., Asraf, H., Chakraborty, M., Elkabets, M., Sekler, I., Taylor, K. M. and Hershfinkel, M. 2018. Enhanced ZnR/GPR39 activity in breast cancer, an alternative trigger of signaling leading to cell growth. Scientific Reports 8(1), article number: 8119. (10.1038/s41598-018-26459-5)

2012

Taylor, K. M., Kille, P. and Hogstrand, C. 2012. Protein kinase CK2 opens the gate for zinc signaling. Cell Cycle 11(10), pp. 1863-1864. (10.4161/cc.20414)
Taylor, K. M., Hiscox, S. E., Nicholson, R. I., Hogstrand, C. and Kille, P. 2012. Protein kinase CK2 triggers cytosolic zinc signaling pathways by phosphorylation of zinc channel ZIP7. Science Signaling 5(210), article number: ra11. (10.1126/scisignal.2002585)

2011

Taylor, K. M., Gee, J. M. W. and Kille, P. 2011. Zinc and cancer. In: Rink, L. ed. Zinc in Human Health. Biomedical and Health Research Vol. 76. Amsterdam: IOS Press, pp. 283-304.
Taylor, K. M., Thornton, J. K., Ford, D. and Valentine, R. A. 2011. Differential subcellular localization of the splice variants of the zinc transporter ZnT5 is dictated by the different C-terminal regions. PLoS ONE 6(8), article number: e23878. (10.1371/journal.pone.0023878)

2010

Thomas, N. B. P., Hutcheson, I. R., Campbell, L., Gee, J. M. W., Taylor, K. M., Nicholson, R. I. and Gumbleton, M. 2010. Growth of hormone-dependent MCF-7 breast cancer cells is promoted by constitutive caveolin-1 whose expression is lost in an EGF-R-mediated manner during development of tamoxifen resistance. Breast Cancer Research and Treatment 119(3), pp. 575-591. (10.1007/s10549-009-0355-8)
Weaver, B. P. et al. 2010. Zip4 (Slc39a4) expression is activated in hepatocellular carcinomas and functions to repress apoptosis, enhance cell cycle and increase migration. PLoS ONE 5(10), article number: e13158. (10.1371/journal.pone.0013158)

2009

Hiscox, S. E. et al. 2009. Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells. Breast Cancer Research and Treatment 115(1), pp. 57-67. (10.1007/s10549-008-0058-6)
Nicholson, R. I., Hutcheson, I. R., Hiscox, S. E., Taylor, K. M. and Gee, J. M. W. 2009. Experimental endocrine resistance: concepts and strategies. In: Hiscox, S. E., Gee, J. M. W. and Nicholson, R. I. eds. Therapeutic Resistance to Anti-Hormonal Drugs in Breast Cancer: New Molecular Aspects and their Potential. Dordrecht: Springer, pp. 1-26., (10.1007/978-1-4020-8526-0_1)
Hogstrand, C., Kille, P., Nicholson, R. I. and Taylor, K. M. 2009. Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation. Trends in Molecular Medicine 15(3), pp. 101-111. (10.1016/j.molmed.2009.01.004)
Ma, X. L. et al. 2009. Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach. Molecular Cancer Therapeutics 8(11), pp. 3108-3116. (10.1158/1535-7163.mct-08-0772)

2008

Taylor, K. M., Vichova, P., Jordan, N. J., Hiscox, S. E., Hendley, R. and Nicholson, R. I. 2008. ZIP7-mediated intracellular zinc transport contributes to aberrant growth factor signaling in antihormone-resistant breast cancer cells. Endocrinology 149(10), pp. 4912-4920. (10.1210/en.2008-0351)
Nicholson, R. I., Hutcheson, I. R., Jones, H. E., Taylor, K. M., Hiscox, S. E. and Gee, J. M. W. 2008. Compensatory signalling induced by anti-hormone and anti-growth factor therapies in breast cancer: a starting point for the development of resistance to targeted therapies.. In: Pasqualini, J. R. ed. Breast cancer: prognosis, treatment and prevention. 2nd ed. London: Informa Healthcare, pp. 123-136.
Taylor, K. M. 2008. A distinct role in breast cancer for two LIV-1 family zinc transporters. Biochemical Society Transactions 36(6), pp. 1247-1251. (10.1042/bst0361247)
Taylor, K. M., Jordan, N. J., Hiscox, S. E., Gee, J. M. W. and Nicholson, R. I. 2008. Zinc transporter HKE4 as a new target in antihormone resistance of breast cancer [Abstract]. Breast Cancer Research 10(s2), article number: P42. (10.1186/bcr1926)
Zahari, N. M., Taylor, K. M. and Nicholson, R. I. 2008. Functional evaluation of members of the LIV-1 family of proteins and their role in breast cancer. EJC Supplements 6(12), pp. 184-184.

2007

Taylor, K. M. et al. 2007. The emerging role of the LIV-1 subfamily of zinc transporters in breast cancer. Molecular Medicine 13(7-8), pp. 396-406.
Zhao, L., Chen, W., Taylor, K. M., Cai, B. and Li, X. 2007. LIV-1 suppression inhibits HeLa cell invasion by targeting ERK1/2-Snail/Slug pathway. Biochemical and Biophysical Research Communications 363(1), pp. 82-88. (10.1016/j.bbrc.2007.08.127)
Nicholson, R. I., Hutcheson, I. R., Jones, H. E., Hiscox, S. E., Giles, M., Taylor, K. M. and Gee, J. M. W. 2007. Growth factor signalling in endocrine and anti-growth factor resistant breast cancer. Reviews in Endocrine and Metabolic Disorders 8(3), pp. 241-253. (10.1007/s11154-007-9033-5)

2006

Hiscox, S. E. et al. 2006. Tamoxifen-resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of [beta]-catenin phosphorylation. International journal of cancer 118(2), pp. 290-301. (10.1002/ijc.21355)

2005

Jones, H. E., Gee, J. M. W., Taylor, K. M., Barrow, D., Williams, H. D., Rubini, M. and Nicholson, R. I. 2005. Development of strategies for the use of anti-growth factor treatments. Endocrine-Related Cancer 12(S1), pp. S173-S182. (10.1677/erc.1.01004)
Taylor, K. M., Vichova, P., Hiscox, S. E. and Nicholson, R. 2005. Zinc-dependant stimulation of Src, EGFR and IGFR signalling pathways in tamoxifen-resistant breast cancer and the role of zinc transporters. Breast Cancer Research and Treatment 94(Supp 1), pp. S162-S162.

2004

Taylor, K. M., Hiscox, S. E. and Nicholson, R. 2004. Zinc transporter LIV-1: a link between cellular development and cancer progression. Trends in Endocrinology and Metabolism 15(10), pp. 461-463.
Taylor, K. M., Johnson, A., Morgan, H. E. and Nicholson, R. I. 2004. Structure-function analysis of HKE4, a member of the new LIV-1 subfamily of zinc transporters. Biochemical Journal 377(1), pp. 131-139. (10.1042/BJ20031183)

2003

Taylor, K. M., Hadley, L. J., Johnson, A., Morgan, H. E. and Nicholson, R. I. 2003. Structure-function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. Biochemical Journal 375(1), pp. 51-59. (10.1042/BJ20030478)

2001

Glynne-Jones, E. M. et al. 2001. TENB2, a proteoglycan identified in prostate cancer that is associated with disease progression and androgen independence. International Journal of Cancer 94(2), pp. 178-184. (10.1002/ijc.1450)

2000

Dunstan, S. L., Sala-Newby, G. B., Fajardo, A. B., Taylor, K. M. and Campbell, A. K. 2000. Cloning and expression of the bioluminescent photoprotein pholasin from the bivalve mollusc Pholas dactylus. Journal of Biological Chemistry 275(13), pp. 9403-9409. (10.1074/jbc.275.13.9403)

1998

Sala-Newby, G. B., Taylor, K. M., Badminton, M. N., Rembold, C. M. and Campbell, A. K. 1998. Imaging bioluminescent indicators shows Ca2+ and ATP permeability thresholds in live cells attacked by complement. Immunology 93(4), pp. 601-609. (10.1046/j.1365-2567.1998.00004.x)

1997

Taylor, K. M., Trimby, A. R. and Campbell, A. K. 1997. Mutation of recombinant complement component C9 reveals the significance of the N-terminal region for polymerization. Immunology 91(1), pp. 20-27. (10.1046/j.1365-2567.1997.00225.x)

1994

Taylor, K. M., Morgan, B. P. and Campbell, A. K. 1994. Altered glycosylation and selected mutation in recombinant human complement component C9: effects on haemolytic activity. Immunology 83(3), pp. 501-506.
Taylor, K. M., Luzio, J. P. and Campbell, A. K. 1994. A method for in vitro synthesis of unglycosylated recombinant complement component C9. Journal of Immunological Methods 167(1-2), pp. 129-137. (10.1016/0022-1759(94)90082-5)

Member of the School's Pharmacology & Physiology Research Discipline.

Research interests

The mechanism of action of zinc transporters
The regulation of intracellular zinc homeostasis
The role of zinc transporters in cell migration
The role of zinc and zinc transporters in cancer progression
The role of zinc transporters in initiating cell division

My main focus is investigating the mechanism of action of cellular zinc transporters, especially the ZIP family (also known as SLC39A). The intention is to substantiate a model for integrated zinc signalling in cells, confirming the key role of zinc transporters, especially ZIP7, and relating the findings to the fundamental biological effects of cellular zinc. These zinc signalling events are thought to be primarily controlled by specific zinc transporters or channels and my recent novel finding that their zinc transport ability can be controlled by phosphorylation, a mechanism previously unprecedented for zinc transporters, will be examined for a direct structural and/or functional relationship with cellular signalling pathways. These events lead to diverse cellular effects on normal processes such as growth, development and migration or, when aberrantly regulated, diseases such as cancer, diabetes and neurodegeneration ensuring that this project has widespread application for normal and disease states.

The primary focus of my research is to understand how zinc transporters work in cells to control intracellular zinc homeostasis. I am especially interested in the 9 human members of the LIV-1 family of zinc transporters and their role in the progression of breast cancer. These studies include the effects of zinc on multiple signalling pathways as well as growth and invasion, all elements known to lead to cancer progression. This can be acheieved by using phospho-kinase arrays in conjunction with site-directed mutagenesis of zinc transporters.

Zinc handling in cells

Two families of zinc transporters enable zinc to traverse biological membranes: The ZnT family of zinc efflux transporters (termed SLC30A) and the ZIP family of zinc influx transporters (termed SLC39A). The ZIP family of zinc transporters generate labile cytosolic zinc and as such have been demonstrated to have wide ranging biological roles both in normal and disease states. Zinc transporter ZIP7, uniquely among ZIP transporters, is located on the ER membrane and we have recently proposed a controlling role for ZIP7 in zinc release from intracellular stores resulting in activation of multiple tyrosine kinases through zinc-mediated inactivation of protein phosphatases. We have demonstrated that ZIP7 requires phopshorylation before it can transport zinc and act as a hub for release fo zinc from stores.

The mechanism of action of the LIV-1 family of zinc transporters

Using computer software to compare protein sequences, I was able to demonstrate that LIV-1 belongs to a new family of zinc influx transporters which totals nine human family members. Computer searches of secondary structure predicted that these molecules contain 8 transmembrane domains, a long extracellular N-terminus, a short extracellular C-terminus, a consensus sequence for the ZIP family of zinc transporters and a consensus sequence for the catalytic zinc-binding site of metalloproteases, (HEXXH, where H = histidine, E = glutamic acid and X = any amino acid). This latter motif was unusual in that it also contained two novel residues (HEXPHE), proline (P) and glutamic acid (E), previously unprecedented in these positions in any other metalloprotease motifs. Searching the non-redundant NCBI database using BLAST and the unique HEXPHEXGD motif of LIV-1, we have identified over 39 sequences from 12 species, including human, mouse, C.elegans, Drosophila, yeast and bacteria, that contain this unique and highly conserved motif. This family has now been termed SLC39A. The members of the LIV-1 subfamily are similar to ZIP superfamily transporters in secondary structure and ability to transport metal ions across the plasma membrane or intracellular membranes. The localisation of some family members to lamellipodiae mirrors cellular location of the membrane-type matrix metalloproteases. These differences to other zinc transporters may be consistent with an alternative role for them in cells, particularly in diseases such as cancer.

The role of zinc transporters in health and disease

The 9 human members of the LIV-1 family of zinc transporters are increasingly being implicated in a variety of disease states, notably neurodegeneration, asthma, prostate cancer and breast cancer. Investigation of how the cellular localisation and tissue specificity of these zinc transporters can alter zinc homeostasis is paramount to understanding the exact role of these transporters in these different disease states.

The role of zinc transporters in cell migration and mitosis

ZIP6 (or LIV-1 as it used to be known) is an oestrogen-regulated gene that has been implicated in metastatic breast cancer. Its detection has been associated with oestrogen receptor positive breast cancer and with the metastatic spread of these cancers to the regional lymph nodes. We have demonstrated a role for both ZIP6 and ZIP10 in promoting cell migration and have now extended this to understand the role that they play in initiating mitosis. This discovery has enabled research using unique ZIP antibodies to prevent or slow cancer growth.

The role of zinc and zinc transporters in breast cancer

We have observed an increased level of intracellular zinc in our 'in house' model of tamoxifen resistant breast cancer. This has initiated an investigation of a potential role for zinc in the activation of signalling pathways observed in these cells as well as in the increase in aggressive behaviour observed in these cells. Through this invetsigation we have demonstrated an importnat role for zinc transporter ZIP7 in driving the growth and activation of tamoxifen-resistant breast cancers. Our discovery that ZIP7 requires phosphorylation before it can release zinc from stores has allowed us to generate a unique phospho-ZIP7 antibody that only recognises ZIP7 when it is actively releasing zinc from stores. This antibody has much potential for clinical use as its activity is aligned to increased cell growth and proliferation.

The discovery that ZIP6 and ZIP10 initiate cell division

ZIP6 and ZIP10 have always been difficult to study due to their high level of regulation in cells. However, we have now discovered the reason for this. Both ZIP6 and ZIP10 form a complex which moves to the cell outisde when the cell is ready to undergo cell division. This complex brings zinc into the cell and that zinc has a very specialist function to trigger the usual pathways of mitosis. Without this zinc influx, cell division does not happen. We have now expanded on this result and generated some novel antibodies which can prevent the zinc influx and thus prevent cell division which are now being examined as a novel cancer treatment.

Collaborators

Cardiff University

Dr. Julia Gee, School of Pharmacy and Pharmaceutical Sciences, Cardiff University
Prof. Richard Clarkson, School of Biosciences, Cardiff Unviersity

UK

Prof Christer Hogstrand, Kings College, London
Prof Wolfgang Maret, Kings College, London
Prof. Iain Ellis, Molecular Medical Sciences, City Hospital, Nottingham: collaboration on clinical breast cancer series
Prof John Robertson, City Hospital, Nottingham: collaboration on clinical breast cancer series

International

Prof. Glen Andrews, Dept of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas, USA
Prof Michal Hershfinkel, Israel
Prof Lothar Rink, Aachen, Germany
Prof Gerold Schmitt-Ulms, Toronto, Canada

Technologies used

Engineering constructs for expression of recombinant proteins in mammalian cells using TOPO-TA cloning and PCR.
Knockdown of protein expression using siRNA
Generation of mutants using site-directed mutagenesis and gene sequencing to enable investigation of key residues in functional activity of different molecules
Use of tags for monitoring expression of recombinant proteins in cells
Use of knockout cell lines generated using crispr technology
Fluorescent and confocal microscopy of multiple probes in live and fixed cells
Proximity Ligation Assay
Phospho-kinase array analysis
Real-time monitoring of Zn2+ concentrations in cells using different zinc specific indicators such as Newport Green, Fluozin-3 and Zinquin.
Design and generation of novel antibodies to zinc transporter proteins
SDS-PAGE, Western Blotting, FACS analysis, immunocytochemistry.
Use of computer software to predict protein function
Use of cancer databases to investigate the role of zinc transporters

Kathryn teaches on all modules of the MSc in Cancer Cell Biology and Therapeutics and has considerable experience of supervising laboratory based student projects

PHT801 MSc Cancer Cell Biology and Therapeutics
PHT802 MSc Cancer Cell Biology and Therapeutics
PHT803 MSc Cancer Cell Biology and Therapeutics
PHT804 MSc Cancer Cell Biology and Therapeutics
PHT805 MSc Cancer Cell Biology and Therapeutics
PHT806 MSc Cancer Cell Biology and Therapeutics
Module leader for PHT804
Supervision of MPharm undergraduate research projects
Supervision of postgraduate PhD students
Supervision of undergraduate PTY students
Supervision of Erasmus students
Supervision of postrgraduate MSc research student projects

Career profile

Kathryn Taylor studied for a PhD in the field of kidney preservation for transplantation at the department of surgery in Kings' College Hospital, Denmark Hill, London.

After a 9 year maternal career break she returned to investigate the role of complement component C9 in arthritis at the department of Medical Biochemistry, Heath Hospital, Cardiff.

Kathryn joined the Tenovus Centre for Cancer Research in 1997 where she has been investigating the role of the LIV-1 family of zinc transporters in breast cancer.

Kathryn moved to the School of Pharmacy and Pharmaceutical Sciences with the Tenovus Unit in 2000 and is still based there.

Kathryn was awarded a Wellcome Trust Univeristy fellowship from 2010-2015 which helped to cement her interest in zinc transporters, especially ZIP7, ZIP6 and ZIP10.

In 2015, Kathryn was employed as a Senior Lecturer in the School of Pharmacy and Pharmaceutical Sciences, where she began to teach on the MSc in Cancer Cell Biology and Therapeutics.

Honours and awards

Awarded the Fredericksen prize for excellence in zinc biology by the International Society for Zinc Biology in 2022
Elected Past President of the International Society for Zinc Biology (ISZB) 2019-2021
Elected President of the International Society for Zinc Biology (ISZB) 2017-2019
Board member of the International Society for Zinc Biology (ISZB) 2013-2017

Professional memberships

An inaugural member of the International Society for Zinc Biology since 2007
An invited member of the editorial advisory panel of the Biochemistry Journal 2004-2010
A member of the Biochemical Society since 2002

Committees and reviewing

Journal and grant reviewer for multiple journals

Current supervision

Georgia Farr

Research student

Ahmed Alzahrani

Research student

Contact Details

TaylorKM@cardiff.ac.uk
+44 29208 75292
Redwood Building, Floor 2, Room 2.47, King Edward VII Avenue, Cardiff, CF10 3NB

Research themes

Specialisms

zinc transporters
Oncology and carcinogenesis
mitosis