RNF144A sustains EGFR signaling to promote EGF-dependent cell proliferation

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Signaling

Background:

• RNF144A is an E3 ligase that degrades DNA-PKcs, an EGFR-interacting protein.
• RNF144A expression correlates with EGFR levels in various cancers, but their relationship is unclear.

Purpose of the Study:

• To investigate the role of RNF144A in regulating EGF/EGFR signaling and EGF-dependent cell proliferation.
• To elucidate the molecular mechanisms underlying the RNF144A-EGFR interaction.

Main Methods:

• Investigated RNF144A-EGFR interaction upon EGF stimulation.
• Assessed EGFR ubiquitination and protein levels following RNF144A manipulation.
• Analyzed EGF-dependent cell cycle progression and proliferation in RNF144A-depleted cells.
• Examined the effect of RNF144A on EGFR intracellular trafficking.

Main Results:

• EGFR ligands induce a DNA-PKcs-independent interaction between RNF144A and EGFR.
• RNF144A promotes EGFR ubiquitination, stabilizes EGFR protein, and prolongs EGF/EGFR signaling.
• RNF144A depletion decreases EGFR expression, impairs EGF signaling, and reduces EGF-dependent cell proliferation.
• RNF144A influences EGFR transport in intracellular vesicles during EGF treatment.

Conclusions:

• RNF144A plays a crucial, previously unrecognized role in positively regulating EGF/EGFR signaling and EGF-driven cell proliferation.
• RNF144A stabilizes EGFR protein and enhances signaling, potentially through regulating EGFR trafficking.
• Targeting RNF144A may offer a therapeutic strategy for cancers dependent on EGFR signaling.