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Cellular Signalling and Human Disease LaboratoryProfessor Tony Tiganis
Telephone: Email: tony.tiganis@med.monash.edu.au
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The laboratory has recently relocated to the vibrant STRIP complex and has access to cutting edge microscopy (www.microimaging.monash.org), proteomics and flow cytometry (www.flowcore.com.au) platforms and an animal house that incorporates a state of the art metabolic phenotyping facility.
Seated Left to Right: Kim Loh (PhD student), Prof Tony Tiganis (Lab Head), Daniel Wehner (Diplom student).
2nd Row Left to Right: Kelly Chew (RA), Shalindi Jayasuriya (Honours student), Teresa Tiganis (RA/Lab manager; part-time), Haiyang Deng (PhD student).
3rd Row Standing Left to Right: Dr Atsushi Fukushima (post-doc), Dr Florian Wiede (post-doc), Dr Ben Shields (post-doc).
Not in Photo: Bree Buszard (PhD student).
Cell cycle
Prof. T. Tiganis
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In order for an organism to grow and develop, the individual cells that make up the tissues and organs need to ‘cycle', duplicate their DNA and accurately divide it into two daughter cells. In cancer, the process of ‘cell cycle' progression is deregulated resulting in uncontrollable growth. Our laboratory is interested in the functions of PTKs and PTPs during cellular division and in the regulation of cell cycle checkpoints. Projects aimed at characterizing the role of PTPs and PTKs in the DNA replication checkpoint response are available.
TCPTP and Breast Cancer
Prof. T. Tiganis
Breast cancer is the most frequent malignancy among women, with an estimated one million new cases per year worldwide. The majority of breast cancers can be classified into those that are estrogen receptor positive and respond to anti-estrogen and those that are ER negative, but express members of the epidermal growth factor receptor (EGFR) family (EGFR/ErbB1, ErbB2-4) of PTKs. In either case, tyrosine phosphorylation-dependent signaling, as mediated by EGFRs, or for example Src family PTKs (SFKs) that propagate ER and EGFR signaling, is critical to the development and progression of breast cancer.
Our laboratory has shown that ErbB1 and SFKs can serve as bona fide substrates for the ubiquitous PTP known as TCPTP. Furthermore, we have shown that TCPTP attenuates the tumorigenicity that is associated with the overexpression/activation of ErbB1 and/or SFKs in tumour cells and the genomic instability that can be associated with PTK hyperactivation. Projects are available to assess TCPTP's potential to act as a tumour suppressor in breast cancer.
PTPs and Glucose Homeostasis
Prof. T. Tiganis
In the last decade type 2 diabetes has reached epidemic proportions and will soon be one of the world most commonest diseases.
The insulin receptor (IR) is a receptor PTK, which upon binding insulin, phosphorylates itself as well target substrates. IR signalling is integral to the maintenance of glucose homeostasis acting in the liver, muscle and adipose tissue to promote glucose uptake, glycogen synthesis and to inhibit glycogenolysis and gluconeogenesis. The resistance of peripheral tissues to insulin action is a major hallmark in type 2 diabetes.
PTPs are key negative regulators of insulin signaling serving to dephosphorylate the IR and the downstream substrates to terminate insulin action. One approach for enhancing insulin sensitivity and alleviating insulin resistance may involve the inhibition of PTPs that otherwise dephosphorylate and inactive the IR. The prototypic PTP1B is a physiological regulator of IR activation and glucose homeostasis and a validated therapeutic target for the treatment of type 2 diabetes. PTP1B acts in the liver and skeletal muscle to inactivate the IR, but not in adipose tissue. Using cell-based approaches we previously identified TCPTP as a negative regulator of insulin signaling. Projects are available to assess the role of TCPTP in glucose homeostasis.
ROS and Insulin Sensitivity
Prof T. Tiganis and A/Prof. M.J. Watt (Dept. of Physiology)
Oxidative stress, or the chronic generation of reactive oxygen species (ROS), is thought to contribute to the progression of various human diseases including type 2 diabetes. In type 2 diabetes, ROS are thought to promote insulin resistance.
Although the excessive production of ROS by mitochondria is detrimental, paradoxically, ROS generated by NADP(H) oxidases at the plasma membrane/endomembranes may be required for normal intracellular signaling. A wide variety of stimuli including insulin can promote the transient generation of ROS. PTPs are key targets of such ‘physiological' ROS. Our recently published studies indicate that ROS may promote insulin sensitivity early in disease onset via the oxidation and inhibition of PTPs. A project examining the physiological versus pathological contributions of ROS to type 2 diabetes is available.
Hypothalamic Control of Body Weight
Prof. T. Tiganis and Prof. M. Cowley (Dept. of Physiology)
Obesity is increasing at an alarming rate worldwide and is a major risk factor for type 2 diabetes, cardiovascular disease and the metabolic syndrome. An important hallmark of obesity is leptin resistance. Leptin acts on POMC, AgRP and NPY neurons in the hypothalamus to activate signaling pathways that suppress food intake, increase energy expenditure, decrease body weight and improve glucose tolerance.
Approaches aimed at overcoming leptin resistance are attractive strategies for combating obesity and type 2 diabetes. One approach may involve the inhibition of PTPs that terminate leptin signalling. Several projects aimed at characterising the role of PTPs in hypothalamic leptin signaling using cell-based and in vivo approaches are available.
PTPs in Drosophila Melanogaster
Prof. T. Tiganis and Dr Coral Warr (Biological Sciences)
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Genome wide analyses have revealed that the majority of genes, particularly metabolic genes, are highly conserved between organisms as distantly related as humans and fruit flies. The insulin signalling pathway is particularly well conserved impacting on cell growth, survival, cell cycle, ageing and reproduction. Our laboratory is interested in characterising the functions of mammalian PTPs in insulin signalling using Drosophila as a model organism. Cell based and fly based genetics projects are available.
These studies are undertaken in collaboration with Dr Coral Warr who is based in Biological Sciences (www.biolsci.monash.edu.au/staff/warr/research.html). Prospective students are encouraged to visit both laboratories.
Three dimensional crystallographic structure of PTP1B in complex with substrates.
Prof. T. Tiganis and Prof. J. Rossjohn
PTP1B regulates insulin signalling and leptin signalling and is therapeutic target for the treatment of type 2 diabetes and obesity. Our goal is to attain crystallographic structures of PTP1B in complex with substrates. Such structures may afford novel opportunities for the development of PTP1B-targeted therapeutic compounds. Honours and PhD projects are available. These studies are undertaken in the department in collaboration with Prof. Jamie Rossjohn (http://research.med.monash.edu.au/rossjohn/).
T cell Receptor (TCR) Signalling
Prof. T. Tiganis
T cells play a central role in the adaptive immune response acting both as direct effectors and as regulatory cells to control the magnitude and duration of an immune response to invading pathogens, tumour cells and modified self-antigens. The primary event leading to T cell activation and differentiation is the triggering of an antigen-specific TCR by a processed foreign antigenic peptide presented by a MHC on the surface of an antigen-presenting cell. Tyrosine phosphorylation is instrumental in TCR signalling. Our preliminary studies indicate that the tyrosine phosphatase TCPTP may be a key negative regulator of TCR signalling and responses. Available projects include: 1) Characterising the mechanism by which TCPTP regulates TCR signalling, 2) Characterising TCPTP's role in T cell development, and 3) Assessing TCPTP's role in T cell responses in vivo using knockout mice.
Tumour Necrosis Factor Signalling
Prof. T. Tiganis
The proinflammatory cytokine tumour necrosis factor (TNF) acts on variety of cell types including macrophages, lymphocytes, keratinocytes and fibroblasts to coordinate immune and inflammatory responses. Inappropriate production of TNF or sustained activation of TNF signalling has been implicated in diverse human disorders including rheumatoid arthritis, inflammatory bowel disease, diabetes and cancer. Our published studies indicate that TCPTP is an important negative regulator of TNF signalling. Projects are available to characterise 1) the mechanism by which TCPTP regulates TNFa signalling, and 2) assess TCPTP’s role in TNF signalling in vivo using knockout mice.
1. Cancer
Flint, A.J., Tiganis, T., Barford, D., and Tonks, N.K. (1997) Development of ‘substrate trapping' mutants to identify physiological substrates of protein tyrosine phosphatases. Proc. Natl. Acad. Sci. USA 94, 1680-1685. (2003 IF = 10.2)
Tiganis, T., Bennett, A.M., Ravichandran, K.S., & Tonks, N.K. (1998) Epidermal growth factor receptor and the adaptor protein p52Shc are specific substrates of the T-cell protein tyrosine phosphatase. Mol. Cell. Biol. 18, 1622-1634. (2003 IF = 8.1)
Klingler-Hoffmann, M., Fodero-Tavoletti, T.M., Mishima, K., Narita, Y., Cavenee, W., Furnari, F.B., Huang, S.H.-J., & Tiganis, T. (2001) The protein tyrosine phosphatase TCPTP suppresses the tumourigenicity of glioblastoma cells expressing a mutant epidermal growth factor receptor. J. Biol. Chem. 276, 46313-46318. (2003 IF = 6.5)
Shields, B., Hauser, C., Bukczynska. P.E. Court N.W., and Tiganis, T. (2008) DNA replication stalling attenuates tyrosine kinase signalling to suppress S-phase progression. Cancer Cell. 14, 166-179. (2007 IF 24.1)
See Press Releases:
Monash researchers uncover cancer survival secrets
http://news.theage.com.au/national/secrets-of-cancer-survival-revealed-20080812-3tp4.html
http://monash.yourguide.com.au/news/local/news/general/research-blooms/1246981.aspx
2. DIABETES AND OBESITY
Galic, S., Klingler-Hoffmann, M., Fodero-Tavoletti, T.M., Puryer, M.A., Meng, T.-C., Tonks, N.K., and Tiganis, T. (2003) Regulation of insulin receptor signalling by the protein tyrosine phosphatase TCPTP. Mol. Cell. Biol. 23, 2096-2108. (2003 IF = 8.1)
Meng, T.C., Buckley D.A., Galic, S.A., Tiganis, T., and Tonks, N.K (2004) Regulation of insulin signaling through reversible oxidation of the protein tyrosine phosphatases TC45 and PTP1B. J. Biol. Chem. 279, 37716-25. (2004 IF = 6.4)
Galic, S., Hauser, C., Kahn, B.B., Haj, F.G., Neel, B.G., Tonks, N.K., and Tiganis, T. (2005) Coordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTP. Mol Cell Biol. 25, 819-29. (2003 IF = 8.1)
Loh, K., Deng, H., Fukushima, A., Cai, X., Boivin, B., Galic, S., Bruce, C., Shields, B.J., Skiba B., Ooms L., Stepto, N., Wu, B., Mitchell, C.A., Tonks, N.K., Watt, M.J., Febbraio, M.A., Crack, P.J., Andrikopoulos, S., and Tiganis, T. (2009) Reactive oxygen species enhance insulin sensitivity. Cell Metabolism. 10, 260-272 (2007 IF 17.2).
This manuscript was the Featured Article of the issue & an ‘Editor’s Choice’ article in Science Signaling [Redox signaling; The sensitive side of ROS (2009) Science Signaling 2, Issue 92 page ec334].
See Press Releases:
www.reuters.com/article/idUSTRE5955Z620091006
www.abc.net.au/am/content/2009/s2706818.htm
3. IMMUNITY AND INFLAMMATION
van Vliet, C., Bukczynska, P.E., Puryer, M.A., Sadek, C.M., Shields, B., Tremblay, M.L., and Tiganis, T. (2005) Selective regulation of TNF-induced ERK signalling by Src family kinases and the T-cell protein tyrosine phosphatase. Nat. Immunol. 6, 253-260 (2005 IF = 28.1)
Lu, X., Malumbres, R., Shields, B., Natkunam, Y., Sarosiek, K.A., Jiang, X., Tiganis, T.,* and Lossos, I.S.* (2008) PTP1B is a negative regulator of interleukin 4-induced STAT6 signaling. Blood. 112, 4098-108. (2007 IF 10.9) * co-corresponding authors
Scholarship support is available to new PhD students. An Honours degree, or Masters by Research degree is essential. The Honours/Masters degree should be in a relevant discipline such as Biochemistry, Cell Biology, Cancer Biology, Physiology, or Immunology.
The student nominated for this scholarship must have completed a four year undergraduate degree, preferably with an H1 assessment and be an Australian or New Zealand citizen,or an Australian permanent resident. The PhD stipend rate is $20,427 p.a. in 2009.
Submit your application containing a short outline of your research interests, your curriculum vitae, transcript of academic results and the contact details of two referees to:
Prof Tony Tiganis
Department of Biochemistry and Molecular Biology
Monash University
Victoria 3800
We also have positions for international students: applicants are advised to check the Graduate office for information on entry requirements scholarships prior to application.
