||松沢健司、池ノ内順一, MAGI-ASPPを介した細胞の収縮力調節による上皮細胞シートの恒常性維持機構, 日本細胞生物学会, 2021.07, Multicellular tissues are covered by a continuous sheet of epithelial cells. The epithelial cells adhere to each other through cell adhesion structures, the apical junctional complexes (AJC), that are reinforced by a network of actomyosin filaments. Contractility of the actomyosin network drives the constriction of the apical plasma membrane, a hallmark of epithelial cells that underlies cell shape changes during developmental morphogenesis and maintenance of tissue integrity in homeostasis. However, it is unclear how the core components of the AJC modulate apical contractility in the broader context of the epithelial cell sheet.
In this study, we present evidence that the membrane-associated guanylate kinases (MAGUK) family proteins MAGI-1 and MAGI-3 are key negative regulators of apical membrane contractility. We find that MAGI knockout in a model epithelial cell line enriches non-muscle myosin IIB (NMIIB) as well as the myosin activator Rho-associated protein kinase 1 (ROCK1) at AJC. As a result of the heightened cellular contractility, the MAGI knockout cell sheet is populated by cells having irregularly sized apical domains. Members of MAGI proteins are differentially recruited to the AJC by the scaffolding proteins afadin and the zonula occludens (ZO) family proteins. MAGI then recruit ankyrin-repeat-, SH3-domain- and proline-rich-region-containing protein 2 (ASPP2), which in turn controls the localizations of the polarity proteins Partitioning defective-3 (Par-3) and atypical protein kinase C (aPKC) at AJC. We further clarify the functional interaction between ASPP2 and Par-3 by elucidating the requirement for ASPP2 recruitment of protein phosphatase 1 (PP1) to retain aPKC at AJC, which is necessary to antagonize ROCK. These results taken together indicate that homeostasis of the epithelial sheet morphology requires conformity of two factors within a certain range by the constituent cells: junctional ROCK activity and NMIIB recruitment. Finally, signaling from AJC to Par-3-aPKC through MAGI is a crucial means of normalizing this activity level, owing to MAGIs’ role in regulating local phosphorylation dynamics through ASPP2-PP1..
||松沢健司、大賀隼人、池ノ内順一, 上皮細胞極性における接着タンパク質ZOとafadinの相乗的作用の解析, 第４２回日本分子生物学会年会, 2019.12.
||松沢健司, アルファカテニンによる集団細胞運動の制御機構, 新学術領域「数理シグナル」第２回若手ワークショップ, 2018.09.
||Kenji Matsuzawa, Takuya Himoto, Yuki Mochizuki, Junichi Ikenouchi, Alpha-catenin controls the anisotropy of force distribution at cell-cell junctions during collective cell migration, 第７０回日本細胞生物学会・第５１回日本発生生物学会合同大会, 2018.06.