Scientists Uncover a Tipping Point in Cells. This Is How Cancer May Begin
CEITEC/Tripsianes Lab: Scientists Uncover a Tipping Point in Cells. This Is How Cancer May Begin
Cells in the human body constantly evaluate signals from their surroundings and decide whether to divide, grow, or remain inactive. One of the key systems controlling this communication is the so-called Wnt signalling pathway. If this mechanism becomes disrupted, cells can spiral out of control, leading to uncontrolled growth and the development of tumours. Scientists from CEITEC and the Faculty of Science at Masaryk University have now described a critical decision-making process – the point at which a cell’s future development is decided. Their findings may, in the future, contribute to the search for ways to slow down or stop such processes in diseases like cancer.
The Wnt signalling pathway is a mechanism that coordinates billions of cells in the body – it is responsible for the development of an entire organism from a single cell, and it continues to regulate tissue renewal throughout adult life. Until now, it was not fully understood how this mechanism works in detail. However, new research by teams from Masaryk University (MUNI) shows that the cells do not respond to stimuli smoothly, but rather operate in an on-off mode once a certain decision-threshold is crossed. This principle changes our understanding of how cells function together and helps explain situations in which cellular decision-making goes out of control and may lead to cancer development.
The process begins at the surface of the cell, where a signal is captured by a receptor embedded in the cell membrane. A protein called Dishevelled (DVL) then binds to this receptor and carries the signal further into the cell. However, for the signal to continue, DVL must first undergo a series of chemical modifications. Small chemical groups begin to accumulate on its surface, progressively increasing its negative charge.
CEITEC/Tripsianes Lab: Scientists Uncover a Tipping Point in Cells. This Is How Cancer May Begin: New mechanism of Wnt signal transduction
And this is where the decisive moment occurs.
“We found that the DVL protein behaves like a switch – its structure changes abruptly once the negative charge on its surface exceeds a certain threshold. Only then does it rearrange and allow the signal to proceed further,” explains first author Miroslav Micka.
At this point, DVL detaches from the receptor, allowing the signal to move deeper into the cell. The cell then receives a clear instruction on how to respond – for example, to start dividing or change its function.
This crucial “tipping point,” where the fate of the signal is decided, has so far been only partially understood: “Scientists knew the pathway the signal follows, but they mostly viewed it as a gradual regulatory system. However, our teams have shown that it is rather a process based on decision points and abrupt changes once a certain threshold is crossed. This is important not only for understanding how cells function, but also for explaining what happens when these processes become dysregulated,” add corresponding authors Konstantinos Tripsianes from CEITEC MUNI and Vítězslav Bryja from the Faculty of Science.
Such decision points in cellular signalling are particularly important from a medical perspective, as their disruption can trigger processes that lead to tumour development. A better understanding of these processes, on the other hand, paves the way for more effective treatments.
The study was published in the journal Science Advances.
CEITEC/Tripsianes Lab: Scientists Uncover a Tipping Point in Cells. This Is How Cancer May Begin: DVL in a cell (green), cell nucleus (blue)
CEITEC/Tripsianes Lab: Scientists Uncover a Tipping Point in Cells. This Is How Cancer May Begin: DVL in a cell (green), enzym modifiyng DVL (red), cell nucleus (blue)
CEITEC/Tripsianes Lab: Scientists Uncover a Tipping Point in Cells. This Is How Cancer May Begin: DVL in a cell (green), enzym modifiyng DVL (red), cell nucleus (blue)
Original article
A Wnt-induced conformational phospho-switch in DVL3 controls association with Frizzled receptors and Wnt/β-catenin signaling
Miroslav Micka, Jitender Kumar, Petra Paclíková, Zuzana Hayek, Kateřina Hanáková, Cherine Bechara, Hana Plešingerová, Ondrej Šedo, Sara Bologna, Elise Del Nero, Kristína Gömöryová, Vojtěch Bystrý, Tomáš Gybel, Tereza Čihalová, Marek Kravec, David Potěšil, Zbyněk Zdráhal, Konstantinos Tripsianes a Vítězslav Bryja.
Sci. Adv., 2026, 12(20), eaed8899
licenced under CC-BY 4.0
Abstract
It is well known that Dishevelled (DVL) phosphorylation by casein kinase 1 (CK1) relays Wnt signals from Frizzled (FZD) receptors to downstream effectors, yet any mechanistic aspects of DVL function related to phosphorylation remain unresolved. Here, we uncovered a Wnt-induced DVL phospho-switch that is mutually exclusive with FZD association. CK1 multiphosphorylation changes dramatically the bulk electrostatics to promote DVL intramolecular interaction between the DEP domain and the adjacent disordered region. A panel of DVL3 mutants demonstrated a switch-like behavior at the molecular level when a charge threshold was reached. Charge accumulation proximal to DEP proved to be a key functional event required, but not sufficient, for Wnt/β-catenin signaling. Proximity interactomics revealed FZD receptors as the prominent effectors of the DVL phospho-switch function consistent with the molecular competition at the DEP interface. By integrating findings at different levels, we propose a universal mechanism, in which Wnt-induced DVL conformational phospho-switch attenuates coresidence with FZDs as a means for downstream signaling events.
