Keratin 8/18 Regulate the Akt Signaling Pathway.

Area of Science:

• Hepatocyte biology
• Intermediate filament proteins
• Cellular signaling pathways

Background:

• Keratin 8 and keratin 18 (K8/K18) form essential heteropolymers in hepatocytes.
• K8/K18 proteins are known to protect liver cells from toxins.
• The interaction between K8/K18 and the Akt survival pathway requires further elucidation.

Purpose of the Study:

• To investigate the role of K8/K18 in regulating the Akt signaling pathway.
• To determine how K8/K18 phosphorylation and mutations affect Akt binding.
• To assess the impact of K8/K18 on Akt signaling and liver protection in vivo.

Main Methods:

• Utilized cultured cell systems to study K8/K18-Akt interactions.
• Examined K8/K18 phosphorylation and K8 mutations (gly-62-cys).
• Compared Akt signaling pathway activity in K18-null and nontransgenic mice with induced liver damage.

Main Results:

• K8/K18-Akt binding is modulated by K8/K18 phosphorylation and K8 mutations.
• K8/K18 expression enhances Akt protein stability in cultured cells.
• K18-null mice exhibit downregulated Akt signaling and increased apoptosis during liver injury, with reduced phosphorylation of downstream factors GSK3β and NFκB.

Conclusions:

• K8/K18 expression is crucial for maintaining Akt signaling pathway integrity.
• K8/K18 plays a protective role in mitigating liver damage by supporting the Akt pathway.
• Modulation of K8/K18 phosphorylation and mutations impacts liver cell survival mechanisms.