Roberto Gabriela Molinari, Boutet Alison, Keil Sarah, Del Guidice Emmanuelle, Duramé Eloïse, Tremblay Michel G, Moss Tom, Therrien Marc, Emery Gregory
Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, P.O. Box 6128, Downtown station, Montréal, QC H3C 3J7, Canada.
St-Patrick Research Group in Basic Oncology, Cancer Division of the Quebec University Hospital Research Centre, Laval University, Québec, QC, Canada.
Dev Cell. 2025 Jan 6;60(1):119-132.e6. doi: 10.1016/j.devcel.2024.09.014. Epub 2024 Oct 10.
Collective cell migration is fundamental in development, wound healing, and metastasis. During Drosophila oogenesis, border cells (BCs) migrate collectively inside the egg chamber, controlled by the Ste20-like kinase Misshapen (Msn). Msn coordinates the restriction of protrusion formation and contractile forces within the cluster. Here, we demonstrate that Tao acts as an upstream activator of Msn in BCs. Depleting Tao significantly impedes BC migration, producing a phenotype similar to Msn loss of function. Furthermore, we show that the localization of Msn relies on its citron homology (CNH) domain, which interacts with the small GTPase Rap2l. Rap2l promotes the trafficking of Msn to the endolysosomal pathway. Depleting Rap2l elevates Msn levels by reducing its trafficking into late endosomes and increases overall contractility. These data suggest that Tao promotes Msn activation, while global Msn protein levels are controlled via Rap2l and the endolysosomal degradation pathway. Thus, two mechanisms ensure appropriate Msn levels and activation in BCs.
集体细胞迁移在发育、伤口愈合和转移过程中至关重要。在果蝇卵子发生过程中，边界细胞（BCs）在卵室内集体迁移，受类Ste20激酶Misshapen（Msn）调控。Msn协调簇内突起形成和收缩力的限制。在这里，我们证明Tao在BCs中作为Msn的上游激活因子发挥作用。耗尽Tao会显著阻碍BC迁移，产生类似于Msn功能丧失的表型。此外，我们表明Msn的定位依赖于其与小GTP酶Rap2l相互作用的citron同源（CNH）结构域。Rap2l促进Msn向内溶酶体途径的运输。耗尽Rap2l通过减少其向晚期内体的运输来提高Msn水平，并增加整体收缩力。这些数据表明，Tao促进Msn激活，而Msn的整体蛋白水平通过Rap2l和内溶酶体降解途径进行调控。因此，两种机制确保了BCs中Msn水平和激活的适当性。
