Amardeep Dhillon
Cell signaling and cancer
We are interested in understanding the molecular mechanisms that govern the activities of the intracellular protein networks that constitute signal transduction pathways. Such pathways link a wide array of extracellular signals to the machinery that regulates basic cellular processes such as transcription, translation and cytoskeletal remodeling. Molecular lesions in signal transduction pathways play a critical role in the pathogenesis of many human diseases, including cancer, AIDS, diabetes and Alzheimer’s.
A major goal of our laboratory is to understand the molecular basis and outcomes of deregulated signal transduction in cancer. Our current studies focus on the Erk MAPK pathway, which is perturbed in about a third of all human cancers. This pathway is important in cancer because it regulates multiple biological processes, including cell growth, proliferation, differentiation, survival and motility.
Most cancer-associated lesions deregulate signaling by upstream components in the pathway, including growth factor receptors, Ras GTPases, and B-Raf kinases. Cells within the tumour environment also often express abnormal levels of cell surface receptors (e.g. EGFR) and/or their ligands, which activate signaling in the Erk MAPK pathway. Once active, Erk MAPKs alter the activities of a large number of proteins. Transcription factors are one major class of downstream targets of Erk MAPK signaling. Thus, we are also attempting understand the functions of key transcription factors involved in mediating the downstream effects of Erk MAPK signaling in tumour cells.
The laboratory is also studying mechanisms regulating the dynamic assembly and disassembly of signaling protein complexes and how these processes are perturbed in cancer. To this end we are developing methods for studying the spatial and temporal assembly of protein complexes. These include methods for fractionating and rapidly isolating protein complexes from cells and analyzing their composition using mass spectrometry. These approaches are being used in combination with our expertise in biochemistry, molecular cell biology and genetics.
Projects
Note: Projects are also available for mid-year entry to the Honours course.
1. Regulation and functions of Raf kinases
Raf kinases are the initiating component of the Erk MAPK pathway. Their activity is tightly regulated by a complex array of mechanisms. This project involves the identification and characterization of proteins that regulate Raf kinase activity.
2. Regulation and functions of the Activator Protein-1 (AP-1) transcription factor complex
The AP-1 transcription factor complex is a major downstream target of Erk MAPK signaling. We are studying how the functions of the AP-1 complex are regulated by its binding partners and how the complex regulates tumour cell invasion.
3. Methods to characterise the spatial and temporal assembly of signaling protein complexes
We are developing methods to identify key components of signaling protein complexes and to probe their functions in regulating cellular processes such as proliferation and migration.
Lab personnel
HeadDr Amardeep DhillonResearch staffDr Julian Pakay (Research Officer) Graduate studentsJeannine Diesch Honours studentsHeidi Ho |
Recent publications
- Dhillon AS, Hagan S, Rath O, Kolch W. (2007) 'MAP kinase signalling pathways in cancer'. Oncogene, 26, 3279–90.
- von Kriegsheim A, Pitt A, Grindlay JG, Kolch W, Dhillon AS (2006) 'Regulation of the Raf/MEK/ERK pathway by protein phosphatase', Nature Cell Biol 8, 1011-1016.
- Pollock CB, Shirasawa S, Sasazuki T, Kolch W, Dhillon AS. (2005) 'Oncogenic K-RAS is required to maintain changes in cytoskeletal organization, adhesion, and motility in colon cancer cells', Cancer Res 65, 1244-1250.
- Dhillon AS, Kolch W. (2004) 'Oncogenic B-Raf mutations: Crystal clear at last', Cancer Cell 5, 303-304
- Dhillon AS, Meikle S, Yazici Z, Eulitz M, Kolch W. (2002) 'Regulation of Raf-1 activation and signaling by dephosphorylation', EMBO J 21, 64-71.