Jim R. Woodgett

Professor
PhD, DundeeSamuel Lunenfeld Research Institute
600 University Avenue, Room 982
Toronto, Ontario M5G 1X5
Phone: 416-586-8811
Email Dr. Jim Woodgett
 
Molecular Analysis of Signalling Pathways: Understanding their Roles in Development and Disease
Our laboratory is studying the molecular pathways via which signals are transmitted from receptors to the cytoplasm and ultimately the nucleus of cells where gene transcription is regulated. We are applying a multi-disciplinary and multi-organismal approach in elucidating the regulatory components involved in signalling via protein phosphorylation with the aim of identifying novel therapeutic targets for treatment of diseases such as cancer, diabetes and neurological disorders.
Survival signalling:
Certain signals can stimulate cells to trigger
apoptotic pathways, while others induce protective effects. Clearly, the propensity of a
cell to live or die is an important factor in tumorigenesis and many cancers are caused by
a reduction in the tendency of a cell to commit suicide. Desensitization of pro- apoptotic
circuitry or up-regulation of survival signals will not only distort the longevity of cells
but will also modulate the efficacy of treatments. We have been studying the role of the
phosphatidylinositol 3' kinase pathway (1) . This
signalling system generates 3' phosphorylated phospholipids at the cell membrane that act
to recruit a series of protein kinases leading to the activation and translocation of an
enzyme termed protein kinase B (PKB/Akt). PKB then phosphorylates key proteins within the
cell, many of which are involved in regulating cell viability. One of these targets is
GSK-3, the same enzyme that is regulated by the Wnt pathway (see below). Using transgenic
mice and mutant flies we have investigated the physiological significance of ativation of
PKB in T cells and the mammary gland (2-4) . In
collaboration with Dr. Armen Manoukian , we
identified a new target of the Drosophila enzyme termed Trachealess which is a master
switch for development of the breathing system of fruit flies (5) . Using inducible activation mutants, we have probed the
mechanisms by which PKB and its upstream kinase, PDK1, are regulated and the consequences
of their chronic stimulation (6) . We are employing
similar approaches to investigate the functions of a related protein kinase termed Serum
and Glucocorticoid-dependent Kinase 3 (SGK3) by generating mammary gland transgenic mice
and by understanding its mechanism of activation ( 7 )
. These animals develop mammary tumours with high penetrance, unlike the activated PKB
mice. We are determining the molecular targets of SGK3 that result in its oncogenic
properties.
Wnt/wingless signalling and cell fate determination:
The Wnt pathway has been highly conserved during evolution and mediates cell fate decisions
and differentiation (8) . The remarkable degree of
similarity in the structure and function of of components of this pathway has allowed use
of genetically tractable organisms such as yeast, mould and fruit flies to determine its
function in complex processes. The pathway involves several cancer related genes including
the tumour suppressor, APC, and beta-catenin. A key regulatory component of this system is
a protein kinase termed Glycogen Synthase Kinase-3 (GSK-3). The fruit fly orthologue is
termed Shaggy or Zeste-White3 and this gene is one of the primary interests of Dr. Manoukian . We have generated knocout mice that
lack each of the two genes that encode GSK-3 in mice (e.g GSK-3beta; (9) and GSK-3alpha (10)
and have also generated mice that harbour conditional alleles of these genes. Using
embryonic stem cells that are defective for both copies of GSK-3alpha and beta, we have
teased apart the molecular mechanisms of specificity of this enzyme to understand how it
contributes to multiple signalling pathways without "crossing wires" (11) . Embryonic stem cells that lack all four alleles of GSK-3 show a
profound block in differentiation capacity (11) . We
are exploiting this property to expand progenitor cells from mice in which the two GSK-3
genes have been engineered as conditional alleles towards the goal of developing
methodologies for culturing specific cell types for repair of lesions and regenerative
medicine. This approach is also allowing assessment of the impact of suppressing
differentiation pathways on the potential and frequency of tumorigenesis as well as the
impact of various signalling pathways (including the Wnt, Notch and PI3K systems) on stem
cell pluripotency and differentiation.
Stress-activated protein kinase pathways:
This pathway (see clickable image map) is
induced by a variety of cellular stresses and impinges on several transcription factors
(12) . We are determining the physiological roles for
this transductory system using small molecule inhibitors, inducible activation systems and
genetically modified cells to understand the functions for different components. In
particular, we are interested in the high conservation of splice variants of these protein
kinases as well as their selective physiological functions.Together, these studies provide
insight into the functions and detection of the control circuits which must be thwarted to
escape normal growth regulation and thus are providing novel targets for therapeutic
intervention in a variety of human diseases.
Further details on the people, projects and funding in the Woodgett lab, please see: http://www.mshri.on.ca
List of Key Publications:
Link to Pubmed Publications-
(All laboratory publications are accessible here ).
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1. Scheid, M.P. and Woodgett, J.R.. (2003) Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett. 546, 108-112. Abstract
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2. Parsons, M.J., Jones, R.G., Tsao, M.S., Odermatt, B., Ohashi, P.S. and Woodgett, J.R. (2001) Expression of active protein kinase b in t cells perturbs both t and b cell homeostasis and promotes inflammation. J. Immunol. 167, 42-48. Abstract
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3. Hutchinson, J.N., Jin, J. Cardiff, R.D., Woodgett, J.R. and  Muller, W.J. (2004) Activation of Akt-1 (PKBalpha) can accelerate ErbB-2 mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Research 64, 3171-3178. Abstract
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4. Hutchinson, J., Jin, J., Cardiff, R.D., Woodgett, J.R. and Muller, W.J. (2001) Activation of Akt (protein kinase B) in mammary epithelium provides a critical cell survival signal required for tumor progression. Mol. Cell. Biol. 21, 2203-2212. Abstract
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5. Jin, J., Anthopoulos, N., Wetsch, B., Binari, R.C., Isaac, D.D., Andrew, D.J., Woodgett, J.R, Manoukian, A.S. (2001) Regulation of Drosophila tracheal system development by protein kinase B. Developmental Cell 1, 817-827.
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6. Scheid, M.P., Marignani, P.A. and Woodgett, J. R. (2002) Multiple phosphoinositide 3-kinase-dependent steps in the activation of protein kinase B. Mol. Cell. Biol. 22, 6247-6260. Abstract .
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7. Tessier, M. and Woodgett, J.R. (2006) Role of the PX domain and phosphorylation in activation of serum and glucocorticoid-regulated kinase-3. J. Biol. Chem. 281, 23978-23989.
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8. Doble, B. W. and Woodgett, J.R. (2003) GSK-3, tricks of the trade for a multi-tasking kinase. J. Cell Sci. 116, 1175-1186. Abstract
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9. Hoeflich, K.P., Luo, J., Rubie, E.A., Tsao, M.S., Jin, O. and Woodgett, J.R. (2000) Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature 406, 86-90. Abstract
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10. MacAulay, K., Doble, B.W., Patel, S., Hansotia, T., Sinclair, E.M., Drucker, D.J., Nagy, A. and Woodgett, J.R. (2007) Glycogen synthase kinase-3α-specific regulation of hepatic glycogen metabolism. Cell Metabolism 6, 329-337.
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11. Doble, B., Patel, S., Wood, G.A., Kockeritz, L.K. and Woodgett, J.R. (2007) Functional redundancy of GSK-3a and b in Wnt/b-catenin signaling in an allelic series of embryonic stem cell lines. Developmental Cell 12, 957-971.
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12. Tibbles, L.A. and Woodgett, J.R. (1999) The stress-activated protein kinase pathways. Cell Mol. Life Sci. 55, 1230-1254. Abstract
 
Graduate Students:
- Yin Fung Eric Ho - PhD program
- Prital Patel - PhD program