Mathematical modeling suggests 14-3-3 proteins modulate RAF paradoxical activation

Area of Science:

• Biochemistry
• Molecular Biology
• Mathematical Biology

Background:

• RAF kinase inhibitors can paradoxically increase RAF signaling (PA).
• Conformational autoinhibition (CA) disruption by RAF inhibitors contributes to PA.
• 14-3-3 proteins are known regulators of RAF CA and dimerization.

Purpose of the Study:

• To mathematically model and experimentally investigate the role of 14-3-3 proteins in RAF inhibitor PA.
• To derive analytical expressions for RAF signal regulation modulated by 14-3-3 proteins.

Main Methods:

• Extended a mathematical model of RAF signaling to incorporate 14-3-3 protein functions.
• Derived analytical expressions for RAF signal regulation.
• Performed experimental validation using forced 14-3-3 expression and evolved resistance assays.

Main Results:

• Mathematical model predicts 14-3-3 proteins can potentiate PA by stabilizing autoinhibited RAF.
• Model suggests 14-3-3 proteins can reduce PA by stabilizing active RAF dimers.
• Experimental data confirmed that increased 14-3-3 expression amplifies PA.
• Increased 14-3-3 expression may contribute to resistance against RAF inhibitors.

Conclusions:

• 14-3-3 proteins play a significant role in modulating RAF inhibitor-induced paradoxical activation.
• 14-3-3 proteins can potentially induce PA even for inhibitors with minimal PA.
• Findings suggest therapeutic targeting of 14-3-3 interactions may be a strategy for overcoming RAF inhibitor resistance.