Regulation of signal response through a novel DKK1 receptor "CKAP4"

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K07311
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Osaka University
• Principal Investigator: Yamamoto Hideki 大阪大学, 大学院医学系研究科, 招へい教授 (20372691)
• Co-Investigator(Kenkyū-buntansha): 佐田 遼太 大阪大学, 大学院医学系研究科, 助教 (60869783)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 小胞輸送 / 受容体 / 小胞体 / 細胞膜

Outline of Final Research Achievements

DKK1 is a secretory protein and promotes tumor cell proliferation, but its receptor has not been identified for a long time. CKAP4 was originally identified as an ER protein. We found that CKAP4 is localized to the cell surface membrane (plasma membrane, PM) of a certain group of cancer cells and that the CKAP4 functions as a DKK1 receptor. We also showed that simultaneous expression of both CKAP4 and DKK1 in human cancers was negatively correlated with prognosis. This indicates that PM localization of CKAP4 is necessary for the DKK1-induced tumorigenesis. In this study, we demonstrated that the dynamic trafficking of CKAP4 between the ER and Golgi is controlled by COPI and COPII, and then the delivery of CKAP4 to the PM from the trans-Golgi is regulated by Annexin A2. These results will provide new insights into the molecular mechanism regulating oncogenic DKK1-CKAP4 signaling and suggest that Annexin A2 represents a therapeutic target of cancer where CKAP4 is present in the PM.

Free Research Field

Wntシグナル経路による細胞応答制御

Academic Significance and Societal Importance of the Research Achievements

細胞増殖を促進するためにDKK1が作用する細胞膜受容体はDKK1の発見以来15年以上にわたって不明であったが、私共が所属する研究室がDKK1受容体としてCKAP4を同定し、DKK1-CKAP4経路による細胞増殖制御を明らかにしてきた。本研究において、CKAP4の小胞体への停留機構や細胞膜への輸送経路を解明し、CKAP4シグナル活性制御の一端を明らかにしたことが学術的意義が高い。私共が作製した抗CKAP4抗体を用いてCKAP4が診断、治療の分子標的になる可能性を見出しており、CKAP4の細胞膜への輸送を制御するAnnexin A2が新規抗がん剤開発の標的となる可能性があり、社会的意義が大きい。