Dysregulation of cell proliferation is a major driver of cancer. Whether a cell grows and divides, remains quiescent, or dies, is determined in large part by its responses to extracellular growth factors, which bind receptors on the cell surface to activate signalling pathways in the cell.
We study the signalling pathways that control the amount of growth factor receptors that are displayed on the cell surface and the amount of growth factors and cytokines being secreted. These controls are important for maintaining the right amount of signalling within the cell and between cells – too much signalling will lead to oncogenesis and too little will lead to senescence or cell death. In healthy cells, signalling by growth factor receptors is held in check by internalisation of the activated receptors and their trafficking to the lysosomes, where they are degraded, but with a small proportion of activated receptors avoiding this by being recycled back to the cell surface. We are identifying the protein trafficking pathways that are dysregulated in cancer and to date, we have identified a major signalling pathway that is dysregulated in multiple solid cancers. We have discovered that the protein tyrosine phosphatase PTPN14 (also called Pez) and its substrate PKCd regulates this balance between recycling and degradation. PTPN14 is mutated in multiple cancers, including breast and colorectal cancers and our studies have shown that it is a suppressor of metastasis. Current studies in the Cell Signalling Lab cover understanding the fundamental mechanisms of receptor trafficking regulated by this PTPN14-PKCd signalling pathway, understanding how dysregulation of this pathway leads to human diseases like cancer, and deciphering how cancers with dysregulation in this pathway and other trafficking abnormalities can be treated. We use state-of-the-art super-resolution microscopy and confocal microscopy techniques to study receptor trafficking in real time, molecular and biochemical approaches to study protein functions and interactions, analyse human cancer specimens to identify cancers with dysregulation in trafficking pathways and use knockout mouse studies to understand the physiological role of the PTPN14-PKCd pathway in normal development and tissue or organ functions.
PhD and Honours projects are available from the Cell Signalling Lab. Current projects include:
- Signalling pathways that control growth factor receptor trafficking
- Dysregulation of protein trafficking pathways in cancers
- The PTPN14-PKCd axis in disease and development
- Developing new strategies to identify cancers with dysregulated receptor trafficking
- New treatments for cancers with dysregulated receptor trafficking
- Targeting treatment resistance and cancer relapse
All interested students should contact A/Prof Yeesim Khew-Goodall to discuss research in the Cell Signalling Lab.
L. Belle, N. Ali, A. Lonic, X. Li, J. L. Paltridge, S. Roslan, D. Herrmann, J. R. W. Conway, F. K. Gehling, A. G. Bert, L. A. Crocker, A. Tsykin, G. Farshid, G. J. Goodall, P. Timpson, R. J. Daly, and Y. Khew-Goodall. The tyrosine phosphatase PTPN14 (Pez) inhibits metastasis by altering protein trafficking. Sci. Signal 8:ra18, 2015.(abstract)(full text)
Bracken CP, Li X, Wright JA, Pillman KA, Lawrence D, Salmanidis M, Anderson MA, Dredge BK, Gregory PA, Tsykin A, Neilsen C, Thomson DW, Yap AS, Jensen KB and Khew-Goodall Y* and Goodall GJ*. Genome-wide identification of miR-200 targets reveals a regulatory network controlling cell invasion. EMBO J 33:2040-56, 2014. * equal author contribution.
Li X, Roslan S, Johnstone CN, Wright JA, Bracken CP, Anderson M, Bert AG, Selth LA, Anderson RL, Goodall GJ, Gregory PA, and Khew-Goodall Y. MicroRNA-200 family members differentially regulate breast cancer cell metastasis through ZEB1-independent, but moesin-dependent pathways.Oncogene 33:4077-4088, 2014.
Paterson EL, Kazenwadel J, Bert AG, Khew-Goodall Y, Ruszkiewicz R, Goodall GJ. Downregulation of the miRNA-200 family at the invasive front of colorectal cancers with degraded basement membrane indicates EMT is involved in cancer progression. Neoplasia 15:180-191, 2013.
Lim YY, Wright JA, Attema JL, Gregory PA, Bert AG, Smith E, Thomas D, Drew PA, Khew-Goodall Y and Goodall GJ. Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem cell-like state. J Cell Science 126:2256-66, 2013.
Paltridge JL, Belle L, Khew-Goodall Y. The secretome in cancer progression. Biochim Biophys Acta;1834(11):2233-41, 2013.
Attema JL, Bert AG, Lim YY, Kolesnikoff N, Lawrence D, Pillman KA, Smith E, Drew PA, Khew-Goodall Y, Shannon MF and Goodall GJ. Identification of an enhancer that controls miR-200b~200a~429 gene expression in breast cancer cells. PLoS One Sep 25;8(9):e75517. doi: 10.1371/journal.pone.0075517. eCollection 2013.