About Associate Professor Thomas Grewal

Our research examines the link between cholesterol/membrane transport and cell signaling in cardiovascular disease and cancer. Utilising a multi-disciplinal approach involving biochemistry, molecular cell biology, and state-of-the-art microscopy, we focus on scaffolding proteins and cellular cholesterol transport as model systems to understand coordination of localization and activity of signaling complexes and receptors.

The Grewal group has an internationally recognized expertise how targeting/scaffolding (annexins) proteins coordinate formation of cholesterol-rich microdomains with recruitment and activation of signaling complexes. This is relevant for various aspects in cardiovascular disease as well as cancer. Over the years, we examined LDL receptor endocytosis and degradation, intracellular cholesterol transport and more recently, the role of LDL-cholesterol for secretory pathways. This has lead to the identification of cholesterol-sensitive SNARE-proteins in exocytic transport routes important for cancer cell migration, which is a current focus of the Grewal group. Other research interests include the role of scaffold proteins and cholesterol in the regulation of EGF receptor signaling in cancer, as well as cholesterol and fatty acid transport in hepatocytes, which is relevant for fatty liver disease and hepatocellular carcinoma. This interface of lipid transport routes, scaffold proteins and cell signaling is still a relatively unexplored area in cell biology provided exciting opportunities to combine advanced microscopy with biochemistry to understand fundamental processes that coordinate spatiotemporal signaling in health and disease.

After completing his PhD on gene regulation in Germany in 1993, Associate Professor Thomas Grewal studied lipoprotein receptors during postdoctoral fellowships at the Heart Research Institute (HRI, Sydney) and the Clinical Research Institute (Montreal, Canada). From 1997-2003, Thomas Grewal led a research group at the University Hospital Eppendorf (Hamburg, Germany) and later (2003-2007) at the Centre for Immunology (CFI, St Vincent's Hospital, Sydney). Thomas Grewal joined the Faculty of Pharmacy in October 2007.
Overall he has published more than 60 manuscripts with more than 1,500 citations, including articles in leading journals (J Biol Chem, Oncogene, Traffic, Mol Biol Cell, Arterio Thromb Vasc Biol, J Cell Sci). Collaborations with leading national/international scientists include C Enrich (Barcelona, Spain), J Heeren (Hamburg, Germany) RJ Daly, P Timpson (Garvan), KA Rye, K Gaus (UNSW). Since being in Australia, he received funding from NHMRC, NHF and Cure Cancer Australia.

Associate Professor Thomas Grewal is currently supervising three PhD, one MPhil and two honours student and is Associate Supervisor of four PhD students.

Selected publications

1. Reverter M, Rentero C, Garcia-Melero A, Hoque M, Vilà de Muga S, Álvarez-Guaita A, Conway J, Wood P, Cairns R, Lykopoulou L, Grinberg D, Vilageliu L, Bosch M, Heeren J, Blasi J, Timpson P, Pol A, Tebar F, Murray RZ, Grewal T, Enrich C. Cholesterol regulates Syntaxin 6 trafficking at the TGN-endosomal boundaries. Cell Reports 7 (2014), 883-97. Co-corresponding author. First study that identifies LDL-cholesterol as regulator of SNARE protein Stx6 localization and trafficking, which determines integrin-dependent cell migration (live imaging, FRAP microscopy, 3D migration/invasion assays, fractionation).

2. Koese M, Rentero C, Kota BP, Hoque M, Cairns R, Wood P, Vilà de Muga S, Reverter M, Alvarez-Guaita A, Monastyrskaya K, Hughes WE, Swarbrick A, Tebar F, Daly RJ, Enrich C, Grewal T. Annexin A6 is a scaffold for PKCα to promote EGFR inactivation. Oncogene 32 (2013), 2858-2872. (IF 7.35, 8 citations). Co-corresponding author. Most relevant contribution to the annexin field. Identifies annexin A6 as a PKC scaffold to regulate EGFR signal complex formation at the plasmamembrane (cell signaling studies, biochemical assays, microscopy).

3. 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 4.65, 46 citations). Co-corresponding author. First study identifying that LDL-cholesterol from late endosomes determines cholesterol levels in the Golgi and at the plasma membrane, with drastic consequences for secretory pathways and organization of cholesterol-rich membrane domains at the cell surface (live imaging, FRAP microscopy, fractionations).

4. Reverter M, Rentero C, Vilà de Muga S, Alvarez-Guaita A, Mulay V, Cairns C, Wood P, Monastyrskaya K, Pol A, Tebar F, Blasi J, Grewal T, Enrich C. Cholesterol transport from late endosomes to the Golgi regulates t-SNARE trafficking assembly and function. Mol Biol Cell 22 (2011), 4108-4123. (IF 4.60, 15 citations). Co-corresponding author. Provides first evidence that links late endosomal cholesterol with SNARE cluster formation at the plasma membrane (TIRF microscopy, fractionations)

5. Heeren J, Grewal T, Laatsch A, Rottke D, Rinninger F, Enrich C, Beisiegel U. Recycling of apoprotein E is associated with cholesterol efflux and high density lipoprotein internalization. J Biol Chem. 278 (2003), 14370-14378. (IF 4.65; 89 citations incl. Nat Rev Neurosci 7, 850-59, 2006). Using live imaging and triple immunofluorescence, this is the first study to show that HDL particles are internalized to associate with cholesterol (fluorescent labeling of lipoproteins, live imaging, fractionations).

6. Lladó A, Timpson P, Vilà de Muga S, Moretó J, Pol A, Grewal T, Daly RJ, Enrich C, Tebar F. PKCδ and calmodulin regulate recycling from the early endosomes through Arp2/3 and cortactin. Mol Biol Cell 19 (2008), 17-29. (IF 4.60, 27 citations). Important study establishing that EGFR recycling is not a default pathway, but a highly regulated process that requires cytoskeletal elements around recycling endosomes to control trafficking of EGFR back to the cell surface (biochemical assays, pull downs, cell signaling, confocal microscopy)

7. Grewal T, Heeren J, Mewawala D, Schnitgerhans T, Wendt D, Salomon G, Enrich C, Beisiegel U, Jäckle S. J Biol Chem 275 (2000), 33806 - 33813. Annexin VI stimulates endocytosis and is involved in the trafficking of LDL to the prelysosomal compartment. (IF 4.65; 74 citations incl. Nat Rev Mol Cell Biol 6, 449-61, 2005). Corresponding author. First evidence showing LDL-induced translocation of AnxA6 to late endosomes, together Diego et al., J Biol Chem. 277 (2002), 32187-94, a new concept in the annexin field.

8. Grewal T, Enrich C. Annexins - Modulators of EGF receptor signalling and trafficking. Cell Signal 21 (2009), 847-858. (IF 4.30, 66 citations). Co-corresponding author. This review for this highly recognized journal acknowledges our significant scientific contribution in the understanding of scaffolds regulating endocytic transport and spatiotemporal signaling of receptors through modulation of microdomain formation.

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 7.216; 44 citations). Corresponding author. Highlighted in Curr Opin Cell Biol, 18, 157-161, 2006 and Cell Calcium, 39, 101-112, 2006. Established the concept of scaffolds promoting dynamic recruitment of signaling proteins, followed by receptor signaling complex organization (biochemical, signaling assays).

10. TG34. Vilà de Muga S, Timpson P, Cubells L, Hegemann A, Evans R, Hayes TE, Tebar F, Pol
A, Daly RJ, Enrich C, Grewal T. Annexin A6 inhibits Ras signalling in EGF receptor overexpressing breast cancer cells. Oncogene 28 (2009) 363-377. (IF 7.35, 37 citations). Co-corresponding author. First evidence showing interaction of Annexin A6 with H-Ras, possibly in cholesterol-rich microdomains, using FRET technology.