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Thomas Grewal

Lecturer, Pharmaceutical Chemistry

Qualifications

Diplom (Honours), PhD, PD (Habilitation)

Contact Details

University of Sydney
Phone: +61 2 9351 8496
Email:
Room S303
Pharmacy Building A15
Faculty of Pharmacy
The University of Sydney
NSW 2006 Australia

Career Profile

Dr. Thomas Grewal did his Honours (Diplom) and PhD in Germany, first at the University of Heidelberg and later at the University of Freiburg, on macrophage gene regulation. A prestigious post-doctoral fellowship from the German Research Council (DFG) enabled him to join the Heart Research Institute (HRI) in Camperdown, Sydney, in 1993–96 to study the regulation of monocyte lipoprotein receptors in atherosclerosis. In 1996 he was awarded a fellowship of excellence from the Quebec Ministry of Education to elaborate on his studies at the Clinical Research Institute (CRI) in Montreal, Canada. Dr. Grewal returned to Germany in 1997 to establish a research group at the University Hospital Eppendorf in Hamburg, Germany, and developed a strong interest in scaffolding/targeting proteins (annexins) regulating endosomal membrane traffic, cholesterol transport and EGF receptor/Ras signaling, which is still the focus of his research. After the completion of the Habilitation in 2003, the highest academic post-doctoral degree in Germany, Dr. Grewal returned to Australia to the Centre for Immunology, St. Vincent’s Hospital, as a group head and senior lecturer (conjoint, UNSW, Faculty of Medicine) in the field of receptor signaling/trafficking and cancer research. Dr. Grewal joint the Faculty of Pharmacy in October 2007.
Since 1997 his contributions to the field include 25 manuscripts, including 14 articles with an impact factor of 5.8 – 7.0 in journals such as J Biol Chem, Oncogene, Traffic, Mol Biol Cell, Arterio Thromb Vasc Biol and BioEssays. He presented his findings at European, American and Australian meetings and received invitations to present seminars both nationally and internationally. Since 2003, he reviews manuscripts for journals including PNAS, Hepatology and Oncogene, and acts as an assessor for national/international granting bodies. Overall Dr. Grewal supervised 17 MD, 7 Honours, co-supervised 6 PhD students and gave tutorials, seminars, practical courses in biochemistry and molecular cell biology. He was involved in the organisation of local meetings, development of under-/postgraduate student programs, student assessments and jury member of PhD defences.
Dr. Grewal has established very productive collaborations with leading scientists in the field, including Prof. Carlos Enrich (Barcelona, Spain), Prof. Roger J. Daly (Garvan Institute of Medical Research), Kerry-Anne Rye (HRI), Prof. Wendy Jessup and Katharina Gaus (UNSW), all of those being Co-Investigators on research projects on scaffolding proteins (annexins) regulating (a) EGF receptor/Ras trafficking and signaling (b) cholesterol transport and (c) caveolin transport and caveolae/lipid raft formation. From 1997-2003 he received funding from german granting bodies (DFG, DAAD). Since being in Australia his work was supported through grants from the NHF, Cure Cancer Australia and UNSW. In 2007, he was awarded 2 NHMRC grants on (1) the regulation of EGFR signaling and (2) Ras signaling and cholesterol efflux from late endosomes.

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Research Interests

(1) Regulation of EGFR/Ras signalling and trafficking
One of the most important signaling cascades that is involved in the development of cancer is the EGFR/Ras/MAPK pathway. EGFR is often overexpressed in breast, ovarian, head and neck, esophageal, bladder and cervical cancers and is common in human glioma, leading to enhanced Ras signaling and cell transformation. Therefore a better understanding of EGFR/Ras inactivation is of great interest and a complex machinery involved in this process has been identified. EGFR initially activates Ras at the plasma membrane (PM) and for signal termination, EGFR is endocytosed and targeted to lysosomes for degradation. Internalized EGFR and Ras still signal from endosomes and it is yet unclear, how Ras inactivation is coordinated at the PM and in endosomal compartments. Ras-specific GTPase activating proteins (GAPs) are the most important inactivators of Ras, but the membrane targeting and contribution of GAPs to downregulate EGFR-induced Ras is poorly understood. Out of the diverse GAP protein family, p120GAP is ubiquitously expressed and can bind to EGFR (ErbB1) and ErbB2, making it a promising candidate to downregulate the EGFR/Ras pathway. p120GAP can bind to the EGFR at the PM and in endosomes. Similarly, Anx6, the targeting protein for p120GAP, translocates to the PM and endosomes, which might ensure p120GAP-mediated Ras inactivation along the endocytic pathway. This project aims to identify the molecular mechanisms and subcellular locations of Anx6/p120GAP-mediated inhibition of EGFR/Ras signaling and compare the ability of different GAPs to inactivate EGFR-induced Ras. These studies will provide fundamental insights in the regulation of EGFR/Ras signal termination, and make a valuable contribution to our understanding of EGFR/Ras–related cancers. Since increased GAP activity could be beneficial to downregulate elevated wildtype Ras activity and de-regulated EGFR, this is a novel approach to identify mechanisms to inhibit a signaling pathway that is a well-known target for therapeutic strategies, which is of utmost importance.
Overall, clinical studies have shown that not all patients respond to treatments targeting the EGFR/Ras pathway, suggesting that co-operating genetic lesions contribute to an insensitivity to certain inhibitors. Thus the establishment of additional markers is desirable to develop molecular profiles from individual tumours and better treatment strategies. Our data suggests that Annexin A6 is downregulated in EGFR overexpressing and estrogen receptor -negative breast cancer cells. Studies are underway to identify if loss of Anx6 could be associated with EGFR/Ras-induced transformation. Ultimately this may lead to the development of Annexin A6 as a marker for subgroups of EGFR/Ras-related cancers.

(2) Ras signaling and stimulation of cholesterol efflux in atherosclerosis
Accumulation of cholesterol in macrophages is a pathological hallmark of early atherosclerotic lesions, known as foam cell formation. Hence the stimulation of cholesterol removal (efflux) from macrophages, to prevent or reverse foam cell formation, has great therapeutic potential. High Density Lipoproteins (HDL) and the major HDL apolipoprotein A-I (apoA-I) stimulate efflux from the plasma membrane (PM) and intracellular compartments, such as early and late endosomes. This requires the activation of HDL/apoA-I receptors, including ABC transporters (e.g. ABCA1) and NPC1, and cellular proteins via poorly understood signaling pathways. Increased evidence points at late endosomes as an important compartment regulating efflux and ABCA1 activity in macrophages. We showed that activation of H-Ras and the Mitogen-activated Protein Kinase (MAPK) pathway (Mek1/2, Erk1/2) stimulates export of cholesterol from late endosomes. This suggests that the Ras/MAPK pathway regulates the activity of proteins that are involved in efflux pathways from this compartment. A better understanding of A signalling mechanisms targeting efflux pathways, possibly involving ABC transporters or NPC1, and B the potential contribution of H-Ras and the MAPK pathway (Mek1/2, Erk1/2) in this process will contribute to develop new therapeutic strategies for enhancing cholesterol removal from cells and ameliorating the effects of atherosclerosis.

(3) Role of Annexin A6 in cholesterol export from late endosomes and caveolae/lipid raft formation
Late endosomes in macrophages are an important compartment regulating cholesterol efflux via ABCA1 and NPC1-dependent pathways. However, the mechanisms by which these transporters facilitate the export of cholesterol from LE are not well understood. Of particular therapeutical interest is PPAR a transcription factor that promotes removal of cholesterol from macrophages via stimulating ABCA1, NPC1/2 expression to increase efflux from late endosomes in human macrophages. To improve our understanding of efflux and treatment strategies, it is important to identify the proteins that modulate cholesterol transporter activity in late endosomes. Annexins are a family of proteins involved in the regulation of membrane transport. We have previously shown that Annexin A6 regulates endocytosis and lysosomal targeting of Low density lipoproteins (LDL) and translocates to cholesterol-enriched late endosomes. Recently we identified that Annexin A6 sequesters cholesterol in late endosomes and interferes with NPC1 activity, thereby perturbing the intracellular distribution of cellular cholesterol and inhibiting the formation of cholesterol-rich membrane domains at the plasma membrane (caveolae). Future studies will address the molecular mechanism how Annexin A6 regulates cholesterol transport and caveolae formation. The physiological relevance of reduced caveolae formation ± Annexin A6 for cholesterol efflux and other aspects important to prevent atherosclerosis, such as NO production and smooth muscle cell proliferation, will be addressed. A better understanding of regulatory proteins modulating the activity of cholesterol transporters in late endosomes, possibly NPC1 and/or ABCA1, will contribute to develop new therapeutic strategies for enhancing cholesterol removal from cells and ameliorating the effects of atherosclerosis.

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Publications

  1. Lladó A, Timpson P, Vilà de Muga S, Moretó J, Pol A, Grewal T, Daly RJ, Enrich C, Tebar F. PKC and calmodulin regulate recycling from early endosomes through Arp2/3 complex and cortactin. Mol Cell Biol, in Press, Oct 24, 2007 as 10.1091/mbc.E07-05-0411. (IF 6.773)
  2. Cubells L, Vilà de Muga S, Tebar F, Wood P, Evans R, Ingelmo-Torres M, Calvo M, Gaus K, Tebar F, Pol A, Grewal T, Enrich C. Annexin A6 induced alterations in cholesterol transport and caveolin export from the Golgi complex. Traffic 8 (2007), 1568-1589. (IF 6.612)
  3. Grewal T, Hegemann A, Vila de Muga S, Enrich C. Annexins regulate EGFR signalling and trafficking. Calcium Binding Proteins 2 (2007), 11-20.
  4. Grewal T, Enrich C. Molecular mechanisms involved in Ras inactivation: the annexin A6-p120GAP complex. Bioessays 28 (2006), 1211-20. (IF 6.787, 2 citations).
  5. Turró S, Estanyol JM, Tebar F, Ingelmo-Torres M, Fernández MA, Albor CV, Gaus K, Grewal T, Enrich C, Pol A. Identification and characterization of Associated with Lipid Droplet protein 1: a novel membrane-associated protein that resides in hepatic lipid droplets. Traffic 7 (2006), 1-16. (IF 6.612, 2 citations).
  6. Grewal T, Tebar F, Pol A, Enrich T. Involvement of targeting and scaffolding proteins in the regulation of the EGFR/Ras/MAPK pathway in oncogenesis. Current Signal Transduction Therapy 1 (2006), 147-167 (1 citation).
  7. Heeren J, Beisiegel U, Grewal T. Apolipoprotein E recycling: Implications for dyslipidemia and atherosclerosis. Arterio Thromb Vasc Biol 26 (2006), 442-448. (IF 6.883, 6 citations; highlighted with ‘special interest’ in Curr Opin Lipidol 17, 602-605, 2006)
  8. Rentero C, Evans R, Wood P, Tebar F, Vila de Muga S, Cubells L, de Diego I, Hayes TE, Hughes WE, Pol A, Rye KA, Enrich C, Grewal T. Inhibition of H-Ras and MAPK is compensated by PKC-dependent pathways in annexin A6 expressing cells. Cell Signal 18 (2006), 1006-1016. (IF 4.887, 2 citations)
  9. Grewal T, Evans R, Rentero C, Tebar F, Cubells L, de Diego I, Kirchhoff MF, Hughes WE, Heeren J, Rye KA, Rinninger F, Daly RJ, Pol A, Enrich C. Annexin A6 stimulates the membrane recruitment of p120GAP to modulate Ras and Raf-1 activity. Oncogene 24 (2005), 5809-5820. (IF 6.582, 9 citations; highlighted with ‘special interest’ in Curr Opin Cell Biol, 18, 157-161, 2006 and Cell Calcium, 39, 101-112, 2006)
  10. Heeren, J.*, Grewal, T.*, Laatsch, A., Becker, N., Rinninger, F., Rye, K.A., and Beisiegel, U. Impaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation. J Biol Chem 279 (2004), 55483-55492. *Both authors contributed equally to this work. (IF 5.808, 11 citations)
  11. Grewal, T., Tebar, F., Pol, A., and Enrich C. Annexin 6 and its role in Ras signalling. Annexins 1 (2004), 62-67 (4 citations).
  12. Laatsch, A., Ragozin, S., Grewal, T., Beisiegel, U., and Heeren J. Differential RNA interference: Replacement of endogenous with recombinant LRP. Eur J Cell Biol 83 (2004), 113-120. (IF 3.039, 8 citations)
  13. Grewal T.*, De Diego I.*, Kirchhoff M.F., Tebar, F., Heeren, J., Rinninger, F., and Enrich C. High density lipoprotein-induced signaling of the MAPK Pathway involves scavenger receptor type BI-mediated activation of Ras. J Biol Chem. 278 (2003), 16478-16481. * Both authors contributed equally to this work. (IF 5.808, 26 citations; highlighted with ‘special interest’ in Curr Opin Lipidol 17, 110-121, 2006.
  14. Heeren, J., Grewal, T., Laatsch, A., Rottke, D., Rinninger, F., Enrich, C., and Beisiegel. U. Recycling of apoprotein E is associated with cholesterol efflux and high density lipoprotein internalization. J Biol Chem. 278 (2003), 14370-14378. (IF 5.808, 30 citations)
  15. de Diego, I., Schwartz, F., Siegfried, H., Dauterstedt, P., Heeren, J., Beisiegel, U., Enrich, C., and Grewal, T. Cholesterol modulates the membrane binding and intracellular distribution of annexin 6. J Biol Chem. 277 (2002), 32187-32194. (IF 5.808, 16 Citations)
  16. Grewal, T., Enrich, C. and Jaeckle, S. Role of annexin VI in receptor-mediated endocytosis, membrane trafficking and signal transduction. Review in ‘Annexins - Biological importance and Annexin-related pathologies’ (2002), 157-171. Eds J.Bandorowicz-Pikula (Landes Bioscience).
  17. Enrich, C., Andres, N., Calvo, M., de Diego, I., Fernandez, M. A., Grewal, T., Llado, A., Pol, A., Pons, M. and Tebar, F. Involvement of the endocytic compartment in signal transduction. Review. In Recent Advances in Biological Chemistry 1 (2002), 75-85.
  18. Heeren, J.*, Grewal, T.*, Jaeckle, S. and Beisiegel, U. Recycling of apolipoprotein E and lipoprotein lipase through endosomal compartments in vivo. J Biol Chem 276 (2001), 42333-42338. * Both authors contributed equally to this work. (IF 5.808, 17 citations; highlighted with ‘special interest’ in Curr Opin Lipidol 13, 119-123, 2002.
  19. Pons, M.*, Grewal, T.*, Rius, E., Schnitgerhans, T., Jaeckle, S. and Enrich, C. Evidence for the involvement of annexin VI in the trafficking between the endocytic compartment and lysosomes. Exp Cell Res 269 (2001), 13 - 22. * Both authors contributed equally to this work. (IF 3.777, 12 citations)
  20. Grewal, T., Priciputu, E., Davignon, J. and Bernier, L. Identification of a g-IFN responsive element in the promoter of the human scavenger receptor A gene. Arterio Thromb Vasc Biol 21 (2001), 825-831. (IF 6.883; 13 citations, highlighted with ‘special interest’ in Curr Opin Lipidol 12, 489-495, 2001.
  21. Pons, M., Tebar, F., Kirchhoff, M., Peiró, S., de Diego, I., Grewal, T. and Enrich, C. Activation of Raf-1 is defective in annexin 6 overexpressing Chinese hamster ovary cells. FEBS Letters 501, 69-73 (2001). (IF 3.372; 6 citations)
  22. Grewal, T. , Heeren, J., Mewawala, D., Schnitgerhans, T., Wendt, D., Salomon, G., Enrich, C., Beisiegel, U. and Jäckle, S. Annexin VI stimulates endocytosis and is involved in the trafficking of LDL to the prelysosomal compartment. J Biol Chem 275 (2000), 33806 – 33813. (IF 5.808; 24 citations)
  23. Bartlett, A.*, Grewal, T.*, de Angelis, E., Myers, S. and Stanley, K.K. ‘Role of the macrophage galactose lectin in the uptake of desialylated LDL.’ Atherosclerosis 153 (2000), 219-230. * Both authors contributed equally to this work. (IF 3.811; 4 citations)
  24. Pons, M., Ihrke, G., Koch, S., Biermer, M., Pol, A., Grewal, T. , Jaeckle, S. and Enrich, C. Late endocytic compartments are major sites of annexin VI localisation in NRK fibroblasts and polarized WIF-B hepatoma cells. Exp Cell Res 257 (2000), 33-47. (IF 3.777; 17 citations)
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