Mechanism underlying the association of actomyosin bundles with adherens junctions in epithelial cells

• Project/Area Number: 20K15793
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: The University of Tokushima
• Principal Investigator: SAKAKIBARA Shotaro 徳島大学, 大学院医歯薬学研究部(医学域), 助教 (80836396)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 細胞間接着 / アドヘレンスジャンクション / アクトミオシン束 / カドヘリン-カテニン複合体 / アファディン

Outline of Research at the Start

上皮細胞は、隣り合う細胞同士が細胞間接着によって接着し、生体の内外を隔てる上皮シートを形成している。上皮シートの機械的強度の維持やリモデリングのためには、細胞間接着装置である接着帯(AJ)のアクトミオシン束(AM束)による裏打ち構造が必須であるが、この裏打ち構造の形成と維持の機構は未だ不明である。研究代表者は前年度に、AJに局在する細胞間接着タンパク質複合体であるカドヘリン-カテニン複合体のAM束への結合活性を制御する因子を見出した。本研究では、この結果に基づいてAJのAM束による裏打ち機構を解明する。

Outline of Final Research Achievements

Actomyosin-undercoated adherens junctions are critical for epithelial cell integrity and remodeling. Actomyosin associates with adherens junctions through αE-catenin complexed with β-catenin and E-cadherin in vivo; however, in vitro biochemical studies in solution showed that αE-catenin complexed with β-catenin binds to F-actin less efficiently than αE-catenin that is not complexed with β-catenin. Although a "catch-bond model" partly explains this inconsistency, the mechanism for this inconsistency between the in vivo and in vitro results remains elusive. We herein demonstrate that afadin binds to αE-catenin complexed with β-catenin and enhances its F-actin-binding activity in a novel mechanism, eventually inducing the proper actomyosin organization through αE-catenin complexed with β-catenin and E-cadherin at adherens junctions.

Academic Significance and Societal Importance of the Research Achievements

上皮細胞は、隣り合う細胞同士が細胞間接着によって接着し、生体の内外を隔てる上皮シートを形成している。この上皮シートの破綻はさまざまな疾患の発症と進行に関わる。本研究成果を端緒として、AM束による上皮シートの機械的強度の維持とリモデリングを担うタンパク質-タンパク質相互作用のネットワークの解明が進むことで、新たな疾患バイオマーカーの開発や創薬標的の創出につながることが期待される。

Research Products

• [Journal Article] s-Afadin binds to MAGUIN/Cnksr2 and regulates the localization of the AMPA receptor and glutamatergic synaptic response in hippocampal neurons (2023)
  • Author(s): Maruo T, Mizutani K, Miyata M, Kuriu T, Sakakibara S, Takahashi H, Kida D, Maesaka K, Sugaya T, Sakane A, Sasaki T, Takai Y, Mandai K
  • Journal Title: J Biol Chem Volume: 299: Issue: 4 Pages: 103040-103040
  • DOI: 10.1016/j.jbc.2023.103040
  • Peer Reviewed / Open Access
• [Journal Article] Identification of lysophosphatidic acid in serum as a factor that promotes epithelial apical junctional complex organization. (2022)
  • Author(s): Sakakibara S, Sakane A, Sasaki T, Shinohara M, Maruo T, Miyata M, Mizutani K, Takai Y.
  • Journal Title: J Biol Chem. Volume: 298 Issue: 10 Pages: 102426-102426
  • DOI: 10.1016/j.jbc.2022.102426
  • Peer Reviewed / Open Access
• [Journal Article] Afadin regulates actomyosin organization through αE-catenin at adherens junctions. (2020)
  • Author(s): Sakakibara S, Mizutani K, Sugiura A, Sakane A, Sasaki T, Yonemura S, Takai Y.
  • Journal Title: J Cell Biol. Volume: 219 Issue: 5
  • DOI: 10.1083/jcb.201907079
  • NAID: 120007132269
  • Peer Reviewed / Open Access