Schematic illustration of dynamic ZO-1 relocalization during collective cell migration. ERK activation propagates through the migrating cell population, and ZO-1, which is normally localized at cell–cell adhesions, transiently relocates to podosomes at the basal surface of cells. ZO-1 accumulated at podosomes promotes force generation and extracellular matrix degradation, thereby regulating invasive cell migration.
Image Credit: KyotoU / Sayuki Hirano
Scientific Frontline: Extended "At a Glance" Summary: Mechanisms of Collective Cell Movement
The Core Concept: Collective cell movement involves cells migrating in coordination with their neighbors during biological processes such as embryonic development and wound healing. Recent discoveries reveal this coordinated movement is facilitated by the scaffolding protein ZO-1 riding waves of ERK signaling activation.
Key Distinction/Mechanism: Unlike prior models that categorized ZO-1 purely as a static cell-to-cell adhesion element, new evidence demonstrates that it dynamically relocates to podosomes at the cell's basal surface. By following ERK activation waves, ZO-1 enhances cellular force generation and extracellular matrix degradation to promote invasive migration.
Major Frameworks/Components:
- ERK Signaling Waves: Biochemical signals that propagate through cellular populations to synchronize collective movement.
- ZO-1 Protein: A scaffolding protein that shifts its functional role from maintaining cell adhesion to facilitating cell invasion depending on its localization.
- Podosomes: Cellular structures located on the basal surface where ZO-1 accumulates to degrade the surrounding environment and generate migratory force.
- Live-Cell Imaging Tools: The use of FRET biosensors and fluorescent tagging to simultaneously track real-time ERK activity and ZO-1 protein localization.
Branch of Science: Cell Biology, Molecular Biology, Biophysics, and Oncology.
Future Application: This research provides foundational knowledge that could inform targeted therapies to block cancer metastasis by disrupting ZO-1 relocation pathways. It also offers potential pathways for improving regenerative medicine and accelerated wound-healing treatments.
Why It Matters: Uncovering how individual cells coordinate as a larger collective bridges a critical knowledge gap, explaining the dual molecular processes that govern both healthy tissue development and aggressive cancer invasion.
Like schools of fish and flocks of birds, our cells can migrate collectively in coordination with their neighbors. This harmonious movement of cells occurs during embryonic development, wound healing, and cancer metastasis. However, because individual cells can sense only limited local information, how they coordinate as a larger collective has remained poorly understood.
Previous studies have demonstrated that this collective migration involves adhesion between cells and waves of ERK signaling activation, named for the ERK proteins involved, and may also be influenced by ZO-1, a scaffolding protein best known for its role in cell-to-cell adhesion. Building on this knowledge, a team of researchers at Kyoto University sought to uncover the elusive mechanism behind collective cell movement.
Using live-cell imaging of Madin-Darby canine kidney cells—model mammalian cells often used in biomedical studies—the researchers directly observed the movement of cell collectives. They simultaneously monitored ERK activity using a FRET biosensor and visualized ZO-1 localization using fluorescently tagged ZO-1.
The team's analysis revealed that ERK activation propagates through the cell population and promotes the relocation of ZO-1 to podosomes, structures found on the basal cell surface, during collective cell migration. Effectively, ZO-1 rides ERK activation waves to the podosomes. The researchers observed that once there, ZO-1 enhances force generation, extracellular matrix degradation, and invasive cell migration.
The team also discovered that ZO-1 contributes to the dynamics of ERK activation, suggesting that it acts as a regulator by linking two important aspects of cell behavior: the mechanism by which cell collectives coordinate their movement, and the mechanism by which cells invade by degrading their surrounding environment. Because these findings provide a molecular connection between these processes, the researchers expect them to contribute to a better understanding of normal biological processes, such as development and wound healing, as well as collective cancer invasion.
"I found it particularly fascinating that ZO-1, which is generally understood as a protein that functions in cell-to-cell adhesion, can move to podosomes at the basal cell surface depending on the state of the cell," says first author Sayuki Hirano.
In the future, the team aims to examine whether the dynamic relocation of ZO-1 observed in cultured cells also occurs in living tissues. They also plan to investigate the molecular mechanism through which ERK signaling regulates ZO-1 localization.
Published in journal: Nature Communications
Title: ZO-1 shuttles between apical junctional complexes and podosomes by riding ERK activation waves
Authors: Sayuki Hirano, Yohei Kondo, Asayuki Kitajima, Noriyuki Kinoshita, Tetsuhisa Otani, Mikio Furuse, Naoto Ueno, and Kazuhiro Aoki
Source/Credit: Kyoto University
Edited by: Scientific Frontline
Reference Number: cbio052526_02