E3 ubiquitin ligases in intercellular communication and carcinogenesis
The responsible for the preclinical work on E3 ubiquitin ligases is Dr Edward Leithe, who leads the "Cell Signaling" project group.
Objectives:
1) Define the role of selected E3 ubiquitin ligases in colorectal cancer pathogenesis and their potential as biomarkers.
2) Identify and functionally characterize E3 ubiquitin ligases that regulate intercellular communication via gap junctions in normal and cancerous cells.
Background:
Ubiquitination is a posttranslational modification where ubiquitin, a small globular protein, is covalently conjugated to a target protein. The reaction is a multistep process involving three classes of enzymes, of which the E3 ubiquitin ligases provide specificity to the system by selecting the substrate protein. The E3 ubiquitin ligases interact with and ubiquitinate protein substrates in a temporally and spatially regulated manner, and these processes are frequently deregulated in human cancers. Several E3 ubiquitin ligases represent attractive drug target candidates. Gap junctions consist of intercellular channels that provide for direct cell-to-cell movement of signaling molecules and ionic currents. Gap junctions have important roles in maintaining cellular homeostasis, and loss of these structures during cancer pathogenesis may contribute to increased cell growth and radio- and chemotherapy resistance.
Ongoing projects:
1) We focus our research on understanding the role of the E3 ubiquitin ligases RNF43 and NEDD4 in colorectal cancer and their potential as biomarkers for this disease. RNF43 has a key role in negatively regulating the WNT signaling pathway by targeting WNT receptors at the cell surface for lysosomal degradation. RNF43 mutations are frequently found in colorectal cancer and have been shown to predict response to anti-BRAF/EGFR therapy in patients with metastatic, microsatellite stable (MSS) colorectal cancer with the BRAFV600E mutation. NEDD4 is a proto-oncogene and an important regulator of PTEN as well as several other tumor suppressor proteins. This is a collaborative project among our three project groups, led by Edward Leithe, Kushtrim Kryeziu and Anita Sveen and also involves collaboration with the Core Facility for Mass Spectrometry at Oslo University Hospital.
2) We investigate the role of the NEDD4 family of E3 ubiquitin ligases in regulating intercellular communication via gap junctions, and how their dysregulation impact on the loss of this type of intercellular communication during cancer development. This project is carried out in the project group of Edward Leithe and involves collaboration with the Core Facilities for Advanced Light Microscopy and Electron Microscopy at the Institute for Cancer Research, Oslo University Hospital.
Selected publications:
Totland, M.Z., Knudsen, L. M., Rasmussen, N. L., Omori, Y., Sørensen, V., Elster, V.W., Stenersen, J.M., Jensen, C.L., Larsen, M., Lade, A., Bruusgaard, E., Basing, S., Kryeziu K., Brech, A., Aasen, T., Lothe. R.A. and Leithe, E. The E3 ubiquitin ligase ITCH negatively regulates intercellular communication via gap junctions by targeting connexin43 for endocytosis and lysosomal degradation. Cellular and Molecular Life Sciences, In press.
Totland, M.Z., Rasmussen, N., Knudsen, L.M and Leithe, E. Regulation of gap junction intercellular communication by connexin ubiquitination: Physiological and pathophysiological implications. Cellular and Molecular Life Sciences, 2020; 77(4), 573-591.
Totland, M. Z., Bergsland, C. H., Fykerud, T.A, Knudsen, L. M., Rasmussen, N. L., Eide, P. W., Yohannes, Z., Sørensen, V., Brech, A., Lothe, R. and Leithe, E. The E3 ubiquitin ligase NEDD4 induces endocytosis and lysosomal sorting of connexin 43 to promote loss of gap junctions. Journal of Cell Science, 2017; 130, 2867-82.
Sirnes, S., Lind, G.E., Bruun, J., Fykerud, T., Mesnil, M., Lothe, R.A., Rivedal, E., Kolberg. M. and Leithe, E. Connexins in colorectal cancer pathogenesis. International Journal of Cancer, 2015; 137, 1-11.
Eide, P.A. Cekaite, L., Danielsen, S.A., Eilertsen, I.A., Kjenseth, A., Fykerud, T.A, Ågesen, T, Bruun, J., Rivedal, E., Lothe R.A. and Leithe, E. NEDD4 is overexpressed in colorectal cancer and promotes colonic cell growth independently of the PI3K/PTEN/AKT pathway. Cellular Signalling, 2013; 25, 12-18.