Role of E3 ubiquitin ligases in mediating the loss of intercellular communication via gap junctions during cancer pathogenesis

Adjacent cells in solid tissues communicate directly with each other by exchanging ions and small molecules via intercellular channels. These channels are assembled into distinct plasma membrane domains known as gap junctions. Gap junction channels are composed of a family of transmembrane proteins called connexins, of which the best-studied member is connexin43. Intercellular communication via gap junctions has important roles in controlling cell growth and differentiation and in maintaining tissue homeostasis. Several members of the connexin protein family have been shown to act as tumor suppressor proteins, and they are frequently downregulated during cancer development. Cell-cell communication via gap junctions is often lost during cancer development, which may contribute to increased cell growth and affect the cellular response to radio- and chemotherapy. We are studying the role of E3 ubiquitin ligases in the regulation of gap junctions and how the malfunction of these processes may contribute to the loss of intercellular communication via gap junctions during cancer pathogenesis and its implications for drug resistance.


Selected publications

Original research articles

Totland, M.Z*., Knudsen, L. M.*, Rasmussen, N. L., Omori, Y., Sørensen, V., Elster, V.W., Jensen, C.L., Lade, A., Bruusgaard, E., Basing, S., Kryeziu K., Brech, A., Aasen, T., Lothe. R.A. and Leithe, E. (2024). The E3 ubiquitin ligase ITCH negatively regulates intercellular communication via gap junctions by targeting connexin43 for lysosomal degradation. Cellular and Molecular Life Sciences; 81, 171. *Shared first authorship

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. (2017). The E3 ubiquitin ligase NEDD4 induces endocytosis and lysosomal sorting of connexin 43 to promote loss of gap junctions. Journal of Cell Science; 130, 2867-82.

Fykerud T.A., Knudsen, L.M., Totland, M.Z., Sørensen, V., Dahal-Koirala, S., Lothe, R.A., Brech, A. and Leithe, E. (2016). Mitotic cells form actin-based bridges with adjacent cells to provide intercellular communication during rounding. Cell Cycle; 15, 2943-2957.

Fykerud, T.A, Kjenseth, A., Sirnes, S., Bruun, J., Omori, Y., Brech, A., Rivedal, E. and Leithe, E. (2012). Smad ubiquitination regulatory factor-2 controls gap junction intercellular communication by modulating endocytosis and degradation of connexin43. Journal of Cell Science; 125, 3966-76.

Kjenseth, A., Fykerud, T.A, Sirnes, S., Bruun, J., Kolberg, M., Omori, Y., Rivedal, E. and Leithe, E. (2012). The gap junction channel protein connexin43 is covalently modified and regulated by SUMOylation. Journal of Biological Chemistry; 287, 15851-61.

Review articles

Totland, M.Z., Omori, Y., Sørensen, V., Kryeziu, K. Aasen, T., Brech, A and Leithe, E. (2023). Endocytic trafficking of connexins in cancer pathogenesis. Biochemica Biophysica Acta (BBA) - Molecular Basis of Disease, 2023; 1869(7): 166812

Totland, M.Z., Rasmussen, N., Knudsen, L.M. and Leithe, E. (2020). Regulation of gap junction intercellular communication by connexin ubiquitination: Physiological and pathophysiological implications. Cellular and Molecular Life Sciences; 77(4), 573-591.

Aasen, T.*, Leithe, E.*, Graham, S., Kameritsch, P. Mayan, M.D., Mesnil, M., Pogoda, K., Tabernero, A. (2019), Connexins in cancer: Bridging the gap to the clinic. Oncogene; 38(23), 4429-4451. *Shared first authorship

Leithe, E., Mesnil, M. and Aasen, T. (2016). The connexin 43 C-terminus: A tail of many tales. Biochemica Biophysica Acta (BBA) - Biomembranes; 1865:133-46.

Leithe, E. (2016). Regulation of connexins by the ubiquitin system: Implications for intercellular communication and cancer. Biochemica Biophysica Acta (BBA) - Reviews on Cancer; 1865:133-46.

Sirnes, S., Lind, G.E., Bruun, J., Fykerud, T., Mesnil, M., Lothe, R.A., Rivedal, E., Kolberg. M. and Leithe, E. (2015). Connexins in colorectal cancer pathogenesis. International Journal of Cancer; 137, 1-11.

Leithe, E., Sirnes, S., Fykerud, T., Kjenseth, A. and Rivedal, E. (2012). Endocytosis and post-endocytic sorting of connexins. Biochemica Biophysica Acta (BBA) - Biomembranes; 1818, 1870-79.

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