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Research

Arieh Katz group

Research interests

Prof. Katz co-directs the UCT/MRC Research Group for Receptor Biology together with Dr. Colleen Flanagan from the School of Physiology, University of the Witwatersrand Medical School.

The Group studies G protein-coupled receptors (GPCRs) which constitute a very large family of receptor proteins, which regulate nearly all communication of the organism and the cell with the environment and include the GnRH receptors, in which we are internationally-recognized leaders. GPCRs are the targets of about 50% of the drugs currently in clinical use and they continue to be suitable targets for development of novel therapeutics. Our focus on the GPCR family of proteins allows us to use our expertise in GPCRs to apply our research to diseases that are prevalent in our own society, particularly HIV/AIDS and cervical cancer, while continuing to work on the GnRH receptors.

The Group's research mandate is to study the structure and function of G protein-coupled receptors and to apply the research to understanding and treating diseases that have major effects on the social and economic welfare of South Africa.

The Group's research is organised into four programmes, each built around a particular receptor and containing several aims/projects. All projects reflect the Group's expertise in G protein-coupled receptors.

The four research programmes are:

Programme 1: GnRH Receptor Structure, Ligand Binding and Activated Receptor Conformations
Programme 2: GnRH Receptors: Genes, Regulation, Signalling and Function
Programme 3: Role of Cyclooxygenases and Prostaglandins in Cervical Cancer and Uterine Pathology
Programme 4: The CCR5 Chemokine Receptor and HIV

 

Prof. Katz studies two families of GPCRs that relate to reproductive health, the gonadotropin-releasing hormone (GnRH) receptors and the prostaglandin E2 (PGE2) receptors, these receptors regulate the reproductive function and better understanding of these receptors will provide new therapeutics for treatment of infertility and various reproductive tract pathologies including cancer.

The GnRH I peptide regulates the reproductive axis via binding to its cognate type I GnRH receptor expressed on gonadotropes of the pituitary gland and regulating the release of the gonadotropic hormones LH and FSH. However, recently, it became apparent that most vertebrate species have a second form of GnRH, termed GnRH II. The second form, is structurally conserved in species ranging from fish to humans. Unlike the GnRH type I peptide which is synthesized and found predominantly in the hypothalamus, the GnRH type II peptide is found also in the extra-hypothalamic regions of the brain and in other tissues. Its structural conservation and its wide tissue distribution suggest that it may have an important function. Recently, the type II GnRH peptide has been implicated in regulating mating behaviour. Prof. Katz's group has cloned the type II GnRH receptor from human, marmoset monkey and frog (Xenopus laevis). Interestingly, the human type II receptor seems to be non-functional. The cloning of the type II GnRH receptor enables the elucidation of the physiological function of type II GnRH and is also be a prelude to the development of type II GnRH analogues and towards this end the group is studying the type II GnRH receptor gene regulation, the signaling cascade initiated by the type II GnRH receptor as well as identifying the ligand binding pocket of the receptor. This work will also facilitate the development of selective GnRH therapeutics that interact with either the type I or type II GnRH receptor, minimising drug side-effects. Lastly, in contrast to the type I GnRH receptor the type II GnRH receptors have a C-terminal tail. Since the C-terminal tail in many G protein-coupled receptors is important for receptor internalization and G-protein independent signaling, Prof. Katz's group is studying the role of the C-terminal tail of the type II GnRH receptor in the internalization, signalling and function of the receptor.

GnRH receptors have been implicated in directly inhibiting growth of tumour cells. This inhibition is induced by GnRH agonists and antagonists. It is thought that GPCRs have multiple distinct conformations and that binding of a ligand (agonist or antagonist) stabilizes a particular ensemble of receptor conformations. Different receptor conformations may preferentially stimulate different signaling pathways and cellular responses. This raises the potential that drugs may be designed to stabilize specific receptor conformations and to modulate only one, or a subset, of the cellular responses stimulated by natural ligands. GnRH receptors have been found in tissues outside of the pituitary. Stimulation of GnRH receptors that occur on certain cancer cells inhibits cell proliferation. Prof. Katz's laboratory is working to establish whether type I or type II GnRH receptors mediate the antiproliferative activity of GnRH and which GnRH analogues stimulate this effect and to elucidate the signaling process underlying the growth inhibitory effect.

Prof. Katz's group is also interested in the role of cyclooxygenases and prostaglandins in neoplastic transformation of the cervix. Cancer of the uterine cervix is reported as being the most common cancer in less developed countries. In South Africa, cervical cancer is the second most common cancer in women, comprising 16.6% of all cancers. It is the most common cancer in black women (31.2%) and coloured women (22.9%). Risk factors for cervical carcinoma include socio-economic and socio-demographic factors leading to low-levels of hygiene, multiple sexual partners and sexually transmitted disease, especially those leading to viral infection of the cervical epithelium by human papilloma virus (HPV) and herpes simplex virus. Numerous studies have demonstrated that epithelial tumours may be regulated in an autocrine/paracrine manner by cyclooxygenase (COX)-enzyme products. Two distinct isoforms of the COX enzyme, COX-1 and COX-2 have been reported. COX-2 and more recently COX-1 were found to be up-regulated in several epithelial carcinomas. This has prompted the suggestion that the increased level of prostaglandins and other eicosanoids present in cancer tissue is a consequence of induced COX enzymes. The COX enzymes, also called prostaglandin endoperoxide synthase catalyse the rate limiting step in the conversion of arachidonic acid to prostaglandin H2 and other eicosanoids including prostaglandin E2 (PGE2). PGE2 mediates its effect on epithelial cell through interaction with G-protein coupled receptors. Four different PGE receptor subtypes have been identified and they utilise alternate and in some cases opposing intracellular signalling pathways. PGE2 has been shown to influence mitogenesis to inhibit apoptosis and to promote growth and metastasis of tumours. More recently, enhanced synthesis of PGE2 resulting from up-regulated COX-2 has been shown to induce malignant change in epithelial cells through immunosuppression, increasing metastatic potential of epithelial cells and promoting angiogenesis. The administration of COX inhibitors such as aspirin and other non-steroidal anti-inflammatory drugs (NSAID) was shown to reverse these effects and reduce the risk of colorectal cancer. However, the cellular mechanism by which COX and PGE2 mediate neoplastic transformation of epithelial cells including of the cervix remain to be elucidated. The overall goal of this project is to elucidate the role of COX enzymes, their synthesized product PGE2 and its cognate receptors (EP1-4) in cervical carcinomas. Prof. Katz's group is studying the expression of COX enzymes and PGE2 receptor in cervical tumours and normal tissue as well as in cell lines derived from cervical tumours. Furthermore, the signaling cascade initiated by the PGE2 receptors is also being investigated in order to identify the molecular signaling process that contributes to tumour development and progression. In addition, following the group’s finding that seminal fluid can stimulate the COX-2/PGE2 pathway in a cervical cell line, suggesting that sexual activity can promote cervical tumorigenesis in women having pre-malignant lesions in their cervix, the group is examining the effect of seminal fluid on cervical explants in culture and on cervical cell lines injected into animal models.

Members of Group

Michael Madziva (PhD) Post-doctoral Fellow
Nosisa Matsiliza (MBChB) PhD student
Aron Abera, (MSc) PhD student
Virginia Davids (MBChB) PhD student
Mushi Matjila (MBChB) PhD student
Jason Sutherland (MSc) PhD student
Marla Coetsee (BSc (Hons)) PhD student
Mei-Chi Chan (BSc (Hons)) MSc student
Alex Salo (BSc (Hons)) MSc student
Pumza Philips (BSc (Hons)) MSc student
Carla Raad (BSc (Hons)) MSc student

 

Selected Publications

Abera AB, Sales KJ, Catalano RD, Katz AA, Jabbour HN.
EP2 receptor mediated cAMP release is augmented by PGF2a activation of the FP receptor via the calcium-calmodulin pathway. 
Cellular Signalling, 2010, 22: 71-79.

Folefoc AT, Fromme BJ, Katz AA, Flanagan CA. 
South African Mutations of the CCR5 Coreceptor for HIV Modify Interaction With Chemokines and HIV Envelope Protein. 
Journal of Acquired Immune Deficiency Syndromes, 2010, 54(4): 352-359.

Minsaas L, Planagumà J, Madziva M, Krakstad BF, Masià-Balagué M, Katz AA, Aragay AM. 
Filamin A Binds to CCR2B and Regulates Its Internalization. 
PLoS ONE, 2010, 5(8): e12212 1-14.

Stewart AJ, Katz AA, Millar RP, Morgan K.
Retention and Silencing of Prepro-GnRH-II and Type II GnRH Receptor Genes in Mammals.
Neuroendocrinology, 2009, 90: 416-432

Fromme BJ, Coetsee M, Van Der Watt P, Chan MC, Sperling KM, Katz AA, Flanagan CA.
High-affinity binding of southern African HIV type 1 subtype C envelope protein, gp120, to the CCR5 coreceptor. 
AIDS Res Hum Retroviruses. 2008 Dec;24(12):1527-36.

Faurholm B., Cochrane S., Millar RP., and Katz AA., (2007). Gene structure and promoter functional analysis of the marmoset type II gonadotropin-releasing hormone receptor. Journal of Molecular Endocrinology, 39 (2): 91-104

Mamputha S, Lu Z-L, Roeske RW, Millar RP, Katz AA, Flanagan CA (2007). Conserved Amino acid residues that are important for ligand binding in the type I GnRH receptor are required for high potency of GnRH II at the type II GnRH receptor. Molecular Endocrinology, 21(1):281-92

Du Toit L, Bennett NC, Katz AA, Kallo I, Coen CW. (2006) Relations between social status and the gonadotrophin-releasing hormone system in females of two cooperatively breeding species of African mole-rats, Cryptomys hottentotus hottentotus and Cryptomys hottentotus pretoriae: neuroanatomical and neuroendocrinological studies. Journal of Comparative Neurology,494(2):303-13

Melissa Muller Sales K.J., Katz A.A., and Jabbour HN. (2006) Seminal plasma promotes the expression of tumorigenic and angiogenic genes in cervical adenocarcinoma cells via the EP4 receptor, Endocrinology, 147(7): 3356-3365.

Ronacher K., Matsiliza N., Nkwanyana N., Pawson A.J., Adam T., Flanagan C.A., Millar R.P. and Katz A.A. (2004) Serine residues 338 and 339 in the carboxyl-terminal tail of the type II gonadotropin-releasing hormone receptor are critical for beta-arrestin-independent internalization. Endocrinology, 145(10):4480-8.

Sales K.J., Katz A.A., Davis M., Soeters R.P., Hofmeyr M., Galio L., Millar R.P. and Jabbour H.N. (2001) Cyclooxygenase-2 expression and Prostaglandin E2 synthesis are upregulated in carcinomas of the cervix: a possible autocrine/paracrine regulation of neoplastic cell function via EP2/EP4 receptors. J Clin Endocrinol Metab., 86: 2243-2249.

Sales, K.J., Katz, A.A., Millar, R.P. and Jabbour, H.N. (2002). Cyclooxygenase-1 is up regulated in cervical carcinomas: autocrine/paracrine regulation of  cyclooxygenase- 2, PGE receptors and angiogenic factors by cyclooxygenase-1. Cancer Research., 60: 424-432.

Sales K.J., Katz A.A., Millar R.P. and Jabbour H.N. (2002) Seminal plasma activates cyclooxygenase-2 and prostaglandin e2 receptor expression and signalling in cervical adenocarcinoma cells. Molecular Human Reproduction, 8: 1065-1070.

Millar R., Lowe, S., Conklin D., Pawson A., Maudsley S., Troskie B., Ott T., Millar M., Lincoln G., Sellar R., Faurholm B., Scobie G., Kuestner R., Terasawa E. and Katz A.A. (2001) A novel mammalian receptor for the evolutionarily conserved Type II GnRH.Proc. Natl. Acad. Sciences. USA. 98: 9636-9641.

Faurholm, B., Millar, R.P. and Katz A.A. (2001) The genes coding for the type II gonadotropin-releasing hormone receptor and the ribonucleoprotein RBM8A in humans overlap in two genomic loci. Genomics, 78: 15-8

 

List of Collaborators

Researcher Department Institution
Colleen A. Flanagan School of Physiology Witwatersrand University, SA
Dr. H. Jabbour MRC Human Reproductive Sciences Unit Edinburgh University, UK
Prof. RP Millar MRC Human Reproductive Sciences Unit Edinburgh University, UK
Prof. A. Aragay Dept. of Cell Biology Bergen University, Norway
Prof. S. G. Graber Dept. of Pharmacology University of Virginia, USA
Prof. N. Bennett Dept. of Zoology and Entomology University of Pretoria, SA
Prof. G. van der Horst Dept. of Biomedicine University of Western Cape, SA
Prof. Z. Van Der Spuy Dept. Obstetrics and Gynaecology UCT & Groote Schuur Hospital
Dr R. Soeters Dept. Obstetrics and Gynaecology UCT & Groote Schuur Hospital
Dr. M Duffield Division of Anatomical Pathology UCT & Groote Schuur Hospital