Dissecting the molecular mechanism of Wnt receptor ubiquitination by RNF43.

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07633
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Hokkaido University
• Principal Investigator: Tsukiyama Tadasuke 北海道大学, 医学研究院, 助教 (20399819)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: RNF43 / Wnt / p53 / tumorigenesis / ubiquitin

Outline of Final Research Achievements

In this research project, we focused on elucidating the regulatory mechanism of the Wnt receptor degradation via the functional switch of RNF43 by its phosphorylation, and the molecular mechanism by which RNF43 gene mutation is involved in carcinogenesis.
On these projects, we have reported that the phospho-switch of RNF43 roles the direction of Wnt signaling to the activation or suppression, and that missense mutations in this switch abolish the function of RNF43 and invert it from a tumor suppressor to an oncogene. These results were published in Nature Communications. Also, we reported a review explaining the outline of Wnt receptor regulation and oncogenesis/onco-therapy in BioEssay. In addition, the results in our research were introduced in the media in several TV news programs and a special program for cancer research/treatment. Therefore, we think that our research was evaluated as well-contributed to the society domestically and internationally.

Free Research Field

Wnt signaling and oncogenesis

Academic Significance and Societal Importance of the Research Achievements

大腸がんは死者数の上位３位以内を占め、また国民の約１割が生涯において大腸がんと診断されることから、日本の医療に大きなインパクトを与えている疾患といえる。また大腸がんは、左側に発生する比較的予後の良いタイプと、右側に発生する予後の悪いタイプに分けられる。本研究で焦点を当てたユビキチン化酵素RNF43の遺伝子変異は左側では殆ど見られないが、右側のがんではこの左側での遺伝子変異とは相互排他的に高頻度に観察される。しかし、その発がんにおける分子的詳細は明らかになっていなかった。本研究にて得られた結果は、予後の悪い右側大腸がんの発症機序を理解した上で、今後の治療方針を決定する上での大きな知見となった。