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Cellular Signalling and Human Disease Laboratory

A cell's ability to respond to its extracellular environment involves a complex and highly organised series of events referred to as cellular signalling. Signalling processes regulate fundamental cellular responses and abrogation of these processes can lead to the development of various human diseases.

Protein tyrosine phosphorylation controls a diverse array of cellular responses including growth, proliferation, differentiation, migration, metabolism and survival. Tyrosine phosphorylation is a reversible, dynamic process controlled by the activities of the protein tyrosine kinases (PTKs) and the competing actions of the protein tyrosine phosphatases (PTPs).

The laboratory's general research interest is in understanding the role of tyrosine phosphorylation-dependent signalling in physiological and pathological processes. Our overall goal is to provide a basis from which rational, mechanism-based strategies can be developed for modulating tyrosine phosphorylation-dependent signalling in diseased states such as cancer, inflammation and diabetes.

To date, the laboratory's research has concentrated on understanding the regulation and function of PTPs, key regulatory enzymes that serve to coordinate fundamental cellular responses to varied extracellular and intracellular inputs. Much of the work has focussed on the widely expressed phosphatase known as TCPTP, but we also work on other PTPs including the prototypic PTP1B as well as Ser/Thr and lipid phosphatases. We use wide array of in vitro cell-based (immortalized/transformed and primary cells) and in vivo (knockout mice and mutant Drosophila strains) approaches to systematically dissect the role of PTPs in varied signalling pathways and biological responses.

 

tony-tiganis-lab-photo-2008

2008 Lab Members

Seated Left to Right: Teresa Tiganis (RA; part-time), Kelly Chew (RA), Haiyang Deng (PhD student).

Standing Left to Right: Ben Shields (post-doc), Joab Hwang (Hons student), Atsushi Fukushima (back; post-doc), Kim Loh (front; PhD student), Xiaochu Cai (Hons student), Florian Wiede (post-doc), Kenneth Wee (Hons student), Daniel Wehner (Diplom student), Tony Tiganis (Lab Head)

Not in Photo: Catherine van Vliet (NHMRC Peter Doherty post-doctoral fellow), Bree Buszard (PhD student), Christine Yang (RA).

 

 

Project Areas

Protein 01

Cell Cycle

In order for an organism to grow and develop, the individual cells that make up the tissues and organs need to "cycle" and duplicate their DNA and accurately divide it into two daughter cells.  In cancer, the process of ‘cell cycle’ progression is perturbed resulting in uncontrollable growth without ‘checkpoints’ which otherwise ensure accurate replication and separation of DNA.  Our laboratory is interested in the regulation of cellular division and cell cycle checkpoints by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs).

PTKs and Cancer

PTKs are hyperactivated in wide variety of human solid tumours and blood malignancies contributing to varied aspects of tumourigenesis including hyperplasia, survival, invasion, metastasis and angiogenesis. For example Src family PTKs (SFKs) are overexpressed and activated in approximately 80% of colon tumours and EGFR family PTKs are overexpressed/activated in the majority of breast and lung carcinomas and primary glioblastomas. Our laboratory is interested in understanding the regulation of oncogenic PTK signalling by PTPs. Current projects include characterising the tumour suppressive potential of TCPTP in SFK- and EGFR receptor-mediated tumourigenesis in vitro and in vivo.

protein3

Insulin Signalling

Insulin is the major hormone responsible for lowering blood sugar levels. The lack of insulin as a result of the degeneration of b cells in pancreatic islets, or the lack of response of target cells to normal circulating insulin levels are the key pathological features of type I and type II diabetes, respectively. Insulin binding to its cell surface transmembrane receptor stimulates autophosphorylation and activation of intrinsic PTK activity and subsequent phosphorylation of insulin receptor substrates.

The control of insulin receptor signalling involves the coordinated action of both positive and negative regulatory proteins. Among the negative regulatory proteins, PTPs play a prominent role and their inhibition mimics several actions of insulin including the stimulation of glucose uptake. The development of drugs capable of inhibiting PTPs may allow for the enhanced or prolonged activation of the insulin receptor and have therapeutic use in the treatment of type II diabetes.

Several PTPs have been implicated in the negative regulation of IR signalling, including the endoplasmic reticulum-associated PTP1B. Indeed, PTP1B-deficient mice exhibit tissue-specific insulin resistance as well as obesity resistance. Our laboratory seeks to characterise the role of PTPs, such as PTP1B and the closely related TCPTP, in the regulation of insulin receptor signalling and glucose uptake.

Our laboratory focuses on the functions of PTPs in insulin signalling.  Current projects include 1) Assessing the spatiotemporal control of insulin receptor regulation by PTPs, and 2) Assessing PTP function in insulin signalling and glucose homeostasis in cell models and in vivo using knockout mice.

 

PTPs in Drosophila Melanogaster

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.  Our laboratory focuses on characterising mammalian PTP function in insulin and JAK/STAT 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 (Monash University).

 
   
Longo & Finch (2003) Science 299, 1342-6

T-cell Receptor (TCR) Signalling

Protein 05

T-cells are principal elements of the adaptive immune system recognising and responding to antigenic determinants of potential hazardous pathogens and toxins. T-cell responses depend on direct interaction of the T-cell receptor with peptide-MHC complexes on antigen presenting cells such as dendritic cells and macrophages. Engagement of the TCR activates an array of intracellular tyrosine phosphorylation-dependent signalling cascades for which SFKs are principal mediators. Our laboratory is interested in understanding the role of PTPs in TCR-mediated SFK signalling and in T-cell development and function. Current projects include 1) Characterising the mechanism by which TCPTP regulates TCR signalling and 2) Assessing TCPTP's role in T-cell responses in vitro and in vivo using knockout mice.

Selected Publications

  1. 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.
  2. Tiganis, T., Flint, A.J., Adam, S.A., and Tonks, N.K. (1997) Association of the protein tyrosine phosphatase TCPTP with nuclear import factor p97. J Biol. Chem. 272, 21548-21557.
  3. Hao, L., Tiganis, T., Tonks, N.K., and Charbonneau, H. (1997) The noncatalytic C-terminal segment of the T-cell protein tyrosine phosphatase regulates activity via an intramolecular mechanism. J. Biol. Chem. 272, 29322-29329.
  4. Tiganis, T., Bennett, A.M., Ravichandran, K.S., and 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.
  5. Tiganis, T.,Kemp, B.E., and Tonks, N.K. (1999) The protein tyrosine phosphatase TCPTP regulates epidermal growth factor receptor mediated and phosphatidylinositol 3-kinase dependent signalling. J. Biol. Chem. 274, 27768-27775.
  6. Price, J.T. Tiganis, T.,Agarwal, A., Djakiew, D., and Thompson, E.W. (1999) Epidermal growth factor promotes MDA-MB-231 breast cancer cell migration through a phosphatidylinositol 3'-kinase and phospholipase C-dependent mechanism. Cancer Res. 59, 5475-5478.
  7. Klingler-Hoffmann, M., Fodero-Tavoletti, T.M., Mishima, K., Narita, Y., Cavenee, W., Furnari, F.B., Huang, S.H.-J., and 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.
  8. Lam, M.H., Fodero-Tavoletti, T.M., Michell, B., Kemp, B.E., Tonks, N.K., and Tiganis, T. (2001) Cellular stress regulates the subcellular localisation of the protein tyrosine phosphatase TCPTP. J. Biol. Chem. 276, 37700-37707.
  9. Klingler-Hoffmann, M., Bukczynska, P., and Tiganis, T. (2003) Inhibition of phosphatidylinositol 3-kinase signalling negates the growth advantage imparted by a mutant epidermal growth factor receptor on human glioblastoma cells. Int. J. Cancer. 105, 331-339.
  10. 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.
  11. Bukczynska P., Klingler-Hoffmann M., Mitchelhill K.I., Lam M.H., Ciccomancini M., Tonks N.K., Sarcevic B., Kemp B.E., and Tiganis, T. (2004) The T-cell protein tyrosine phosphatase is phosphorylated on Ser-304 by cyclin-dependent protein kinases in mitosis. Biochem J. 380, 939-49.
  12. 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.
  13. Shimizu, T., Miyakawa, Y., Iwata, S., Kuribara, A., Tiganis, T., Morimoto,C., Ikeda, Y., Kizaki, M. (2004) A novel mechanism for imatinib mesylate (STI571) resistance in the CML cell line KT-1: Role of TC-PTP in modulating signals down-stream from the BCR-ABL fusion protein. Exp. Hematol. 32, 1057-63.
  14. 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.
  15. Fodero-Tavoletti, M.T., Hardy, M.P., Cornell, B., Katsis, F., Sadek, C.M., Mitchell, C,A., Kemp, B.E., and Tiganis, T. (2005) Protein tyrosine phosphatase hPTPN20a is targeted to sites of actin polymerisation. Biochem J. 389, 343-354.
  16. van Vliet, C., Bukczynska, P.E., Puryer, M.A., Sadek, C.M., Shields, B., Tremblay, M.L., 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.
  17. Lu, X., Chen, J., Sasmono, T., His, E.D., Sarosiek, K.A., Tiganis T., & Lossos, I.S. (2007) TCPTP, distinctively expressed in ABC-like diffuse large B-cell lymphomas, is the nuclear phosphatase of STAT6.  Mol. Cell. Biol. 27, 2166-79.
  18. Tiganis, T., & Bennett, A.M. (2007) Protein tyrosine phosphatase function: the substrate perspective.  Biochem J. 402, 1-15
  19. Xiaoqing Lu, Raquel Malumbres, Benjamin Shields, Yasodha Natkunam, Kristopher  A Sarosiek, Xiaoyu Jiang,  Tony Tiganis*, Izidore S Lossos* (2008) PTP1B is a negative regulator of interleukin 4-induced STAT6 signaling. Blood. In press.
    * co-corresponding authors
  20. Shields, B., Court N.W., Hauser, C., Bukczynska. P.E. & T. Tiganis (2008) Cell cycle-dependent regulation of SFK, JAK1 and STAT3 signalling by the protein tyrosine phosphatase TCPTP. Cell Cycle. In press  
  21. Shields, B., Hauser, C., Bukczynska. P.E. Court N.W., & T. Tiganis (2008) DNA replication stalling attenuates tyrosine kinase signalling to suppress S-phase progression.  Cancer Cell. 14, 166–179.

See Press Releases:

http://www.med.monash.edu.au/news/2008/cancer-survival.html

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)

Funding

  • Diabetes Australia
  • National Health and Medical Research Council of Australia

PhD Scholarships

A PhD postgraduate scholarship is available for an Australian citizen or permanent resident with a H1 or H2A Honours degree.

Projects in the laboratory focus on the role of protein tyrosine phosphatases in cellular signaling processes that are perturbed in diseased states such as cancer, inflammatory disorders and type 2 diabetes.

The scholarship provides a tax free stipend of $20,007 p.a. for 2008.

Contact and applications to A/Prof Tony Tiganis.

Prospective students who are likely to obtain first class Honours are also encouraged to visit the lab; 'Top-ups' to PhD stipends will be considered.

International students with degrees equivalent to a Bachelor of Science with Honours degree are encouraged to contact the Dr Tiganis and apply for an International Scholarship (these scholarships provide a stipend and tuition fees). These scholarships are highly competitive and are restricted to students with first class undergraduate marks.

Contact Details

A/Prof Tony Tiganis

Department of Biochemistry and Molecular Biology
Building 13D, Monash University, Victoria 3800, Australia

Tel: +61 3 9905 3772 (Office)
Tel: +61 3 9905 5784 (Lab)
Fax: +61 3 9905 4699
Email: tony.tiganis@med.monash.edu.au