The mitogen-activated protein kinase network, wired to dynamically function at multiple scales
Paolo Armando Gagliardi1, Olivier Pertz1
1Institute of Cell Biology, University of Bern, Baltzerstrasse 4, 3012 Bern, Switzerland.
Abstract:
The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling network is a key transducer of signals from various receptors, including receptor tyrosine kinases (RTKs). It controls cell-cycle entry, survival, motility, differentiation, as well as other fates. After four decades of studying this pathway with biochemical methods, the use of fluorescent biosensors has revealed dynamic behaviors such as ERK pulsing, oscillations, and amplitude-modulated activity. Different RTKs equip the MAPK network with specific feedback mechanisms to encode these different ERK dynamics, which are then subsequently decoded into cytoskeletal events and transcriptional programs, actuating cellular fates. Recently, collective ERK wave behaviors have been observed in multiple systems to coordinate cytoskeletal dynamics with fate decisions within cell collectives. This emphasizes that a correct understanding of this pathway requires studying it at multiple scales.
Insights
The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway exhibits dynamic behaviors like pulsing and oscillations. Understanding these complex signaling dynamics across multiple scales is crucial for cell fate decisions.
Area of Science:
- Cell Biology
- Molecular Signaling
- Systems Biology
Background:
- The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is a critical signaling network.
- It regulates fundamental cellular processes including cell cycle, survival, and differentiation.
- Traditional biochemical methods have limitations in capturing pathway dynamics.
Purpose of the Study:
- To explore the dynamic behaviors of the ERK signaling network.
- To understand how receptor tyrosine kinases (RTKs) influence ERK dynamics through feedback mechanisms.
- To investigate the role of ERK dynamics in cell fate decisions at both single-cell and collective levels.
Main Methods:
- Utilizing advanced fluorescent biosensors to visualize ERK activity in real-time.
- Employing biochemical assays to analyze feedback mechanisms within the MAPK network.
- Observing and analyzing collective ERK wave behaviors in cellular systems.
Main Results:
- Fluorescent biosensors revealed dynamic ERK behaviors like pulsing, oscillations, and amplitude modulation.
- Specific feedback mechanisms from different RTKs encode distinct ERK dynamics.
- Collective ERK wave behaviors were observed to coordinate cytoskeletal dynamics and cell fate decisions.
Conclusions:
- The ERK signaling network exhibits complex, dynamic behaviors essential for cellular functions.
- Understanding these dynamics requires multi-scale analysis, from molecular interactions to collective cell behaviors.
- ERK dynamics play a key role in actuating cellular fates through cytoskeletal and transcriptional regulation.
Related Concept Videos
MAPK Signaling Cascades
Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Amplifying Signals via Enzymatic Cascade
PI3K/mTOR/AKT Signaling Pathway
mTOR Signaling and Cancer Progression
The mTOR pathway or the...
Mitogens and the Cell Cycle


