Mutant p53 amplifies a dynamin-1/APPL1 endosome feedback loop that regulates recycling and migration

Area of Science:

• Cell Biology
• Cancer Research
• Molecular Biology

Background:

• Cancer progression involves altered endocytic trafficking and cell surface receptor signaling.
• Gain-of-function (GOF) mutant p53 influences these processes, impacting cancer cell behavior.

Purpose of the Study:

• To investigate the role of dynamin-1 (Dyn1) in GOF mutant p53-driven cancer cell migration.
• To elucidate the mechanisms by which Dyn1 and associated signaling pathways contribute to metastasis.

Main Methods:

• Quantification of peripherally localized early endosomes.
• Measurement of rapid integrin recycling dynamics.
• Analysis of dynamin-1 (Dyn1) and APPL1 recruitment to endosomes.
• Assessment of Akt signaling modulation and feedback loops.

Main Results:

• Dynamin-1 (Dyn1) is upregulated by GOF mutant p53 at mRNA and protein levels.
• Dyn1 facilitates APPL1 scaffold recruitment to perimeter endosomes.
• Perimeter APPL1 endosomes modulate Akt signaling, creating a positive feedback loop with Dyn1.
• This loop enhances EGFR and β1 integrin recycling, focal adhesion turnover, and cell migration.

Conclusions:

• Dynamin-1 (Dyn1) and Akt-dependent perimeter APPL1 endosomes integrate signaling and receptor trafficking.
• This nexus is amplified in mutant p53-driven cancers, promoting increased cell migration and invasion.
• Targeting this pathway could offer therapeutic strategies for metastatic cancers.