PhD, McMaster University
At a Glance
- Our research focuses on the molecular structure, cellular functions and interaction networks of modular adaptor proteins that regulate oncogenic signalling pathways.
- Ongoing projects in the laboratory include regulation and activation mechanisms of ubiquitin ligases, investigation of the oncogenic signalling pathways that control alternative splicing, and the role of modular adaptors and their isoforms in the activation of unique oncogenic signalling pathways that drive cancer progression.
- We use a range of approaches including proteomics, structural biology, high-throughput and genome wide screens, cell culture, imaging and in vivo models.
- Together with clinical and industry collaborators we work towards translating discovery of specific molecular signalling events into strategies for drug discovery.
The primary interest of our group is understanding the nature and function of specific protein-protein interactions and protein networks in normal cellular function and disease states. With a focus on the molecular structure, cellular functions and interaction networks of modular adaptor proteins we investigate the mechanisms that regulate critical oncogenic signaling pathways. Currently our research is focused in three main areas:
Regulation of ubiquitin ligase function
CBL is a RING type E3 ubiquitin ligase that functions as a central regulator of tyrosine kinase signaling and loss of CBL function is implicated in several forms of leukemia. We have used structural analysis as well as functional studies in primary hematopoietic cells to determine that the SLAP2 adaptor regulates the ubiquitin ligase activity of CBL, through binding induced conformational changes. Our data also show that this novel mode of interaction is important for ubiquitin dependent regulation of tyrosine kinase signaling in hematopoietic cells. Based on this knowledge we are developing high-throughput screening approaches to identify compounds that bind and activate CBL and ubiquitin dependent down regulation of tyrosine kinases and thereby suppress leukemic cell growth.
Regulation of alternative splicing and oncogenic protein isoform expression.
Signal-induced changes in alternative splicing regulate cellular responses, and oncogenic signaling results in expression of a protein isoform with altered functions. Alternative splicing of the adaptor protein NUMB is a critical event in multiple cancer types include lung and breast. Using alternative splicing reporters and high throughput cell based assays we identified the signaling pathways that control NUMB splicing and protein isoform expression. Our current work will determine the global changes in splicing that are coordinately regulated by these pathways in tumor cells and identify novel compounds to inhibit oncogenic splicing events.
Tissue specific adaptor protein expression in cancer cell signaling.
To determine how tissue specific and alternatively spliced protein isoforms can remodel signaling networks and regulate oncogenic signaling we are using CRISPR gene editing and proteomic approaches to comparatively map the phospho-protein profile and interaction networks associated with GADS and NUMB adaptor protein isoforms in both cell culture models and patient samples. In addition, the function of adaptor isoform specific interaction networks in tumour development is being investigated using tumour xenograft and transgenic models.
More information can be found by visiting our website.
- Zhang, Y., Dho, S.E., Othman, K., Simpson, C.D., Lapierre, J., Bondoc, A., C.J. McGlade. (2022). Numb exon 9 inclusion regulates ITGb5 surface expression and promotes breast cancer metastasis. Oncogene.Apr;41(14):2079-2094.
- Wybenga-Groot, L.E., Tench, A., Simpson, C.D., Taylor, P., St. Germain, J., Raught, B., Moran, MF, and C. J. McGlade. (2021) SLAP2 adaptor binding disrupts c-CBL autoinhibition to activate ubiquitin ligase function. J. Mol Biol. Apr 16;433(8):166880
- Wybenga-Groot L.E. and C. J. McGlade. (2021) Sleuthing biochemical evidence to elucidate unassigned electron density in a CBL-SLAP2 crystal complex. Acta Crystallogr F Struct Biol Commun. 2021 Feb 1;77(Pt 2):37-46.
- Dho S.E. Silva- Gagliardi, N., Morgese, F., Berry, D.M, Lamereaux, E., Coyaud, E. Raught, B and C. J. McGlade (2019) Proximity interactions of the ubiquitin ligase Mindbomb reveal a role in regulation of epithelial polarity complex proteins. Scientific Reports Aug 28;9(1):12471.
- Sharma, N., Ponce, M., Kaul, S. Pan, Z., Eiwegger, T., and C.J. McGlade. (2019) SLAP is a negative regulator of FcεRI receptor-mediated signaling and allergic response, Frontiers in Immunology. May 15;10:1020. doi: 10.3389/fimmu.2019.01020.
- Scott BM, Wybenga-Groot LE, McGlade CJ, Heon E, Peisajovich SG, Chang BSW. (2019) Screening of Chemical Libraries Using a Yeast Model of Retinal Disease. SLAS Discov. Dec;24(10):969-977.
- Lynn, B.D., Li, X., Hormuzdi, S.G., Griffiths, E.K., McGlade, C.J. and J.I. Nagy. (2018) E3 ubiquitin ligases LNX1 and LNX2 localize at neuronal gap junctions formed by connexin36 in rodent brain and molecularly interact with connexin36. European Journal of Neuroscience. Nov;48(9)3062-3081.
- Smith, T.L., Van Slyke, P., Jones, N., Dumont, D.J.,and C. J. McGlade (2018) Tie2 signalling through Erk1/2 regulates TLR4 driven inflammation. Cellular Signaling. Nov;51:211-221. doi: 10.1016/j.cellsig.2018.08.001