Pathway crosstalk enables cells to interpret TGF-β duration.

Area of Science:

• Cellular signaling and systems biology
• Molecular mechanisms of cell fate determination
• Quantitative and computational biology

Background:

• Cells detect and transmit temporal signal information, but how stimulus duration is interpreted remains unclear.
• SNAIL1 is a key transcription factor regulating cell fate processes like apoptosis and epithelial-to-mesenchymal transition.
• Transforming growth factor-beta (TGF-β) signaling pathways play critical roles in cellular responses.

Purpose of the Study:

• To investigate how cells interpret the duration of TGF-β stimuli.
• To elucidate the molecular mechanisms underlying SNAIL1 expression regulation by TGF-β.
• To analyze the role of glycogen synthase kinase 3 (GSK3) in TGF-β signaling dynamics.

Main Methods:

• Integrated quantitative and computational analysis of TGF-β induced SNAIL1 activation.
• Pathway analysis to identify crosstalk between SMAD and GLI1 signaling.
• Observation and modeling of GSK3 molecule localization and phosphorylation states.
• Inhibition experiments to validate network motif functions.

Main Results:

• Crosstalk between TGF-β activated pathways forms a SMAD-to-GLI1 relay, controlling SNAIL1 expression.
• SNAIL1 acts as an integrator of TGF-β signal duration, leading to transient or sustained expression.
• TGF-β induces GSK3 accumulation in active and inactive forms in specific cellular compartments.
• A GSK3-GLI1 network motif provides robustness and precise timing to the signaling relay.

Conclusions:

• The identified signaling network acts as a temporal checkpoint, allowing cells to respond appropriately to stimulus duration.
• The GSK3-GLI1 motif ensures robust and timely regulation of SNAIL1 expression in response to TGF-β.
• This study provides insights into the fundamental mechanisms of cellular temporal information processing and its impact on cell fate.