Epidermal growth factor receptor (EGFR) signaling requires a specific endoplasmic reticulum thioredoxin for the post-translational control of receptor presentation to the cell surface

Area of Science:

• Cell Biology
• Molecular Oncology
• Biochemistry

Background:

• Epidermal growth factor receptor (EGFR) is a key regulator in development and a target in cancer therapy.
• Current understanding of EGFR regulation primarily focuses on ligand binding and kinase activity.

Purpose of the Study:

• To investigate the role of anterior gradient homolog 2 (AGR2) in EGFR trafficking and signaling.
• To explore AGR2 as a potential therapeutic target in EGFR-driven cancers.

Main Methods:

• Utilized NCI-H460 lung and A431 epidermoid cancer cell lines.
• Assessed the impact of reduced AGR2 levels and active site mutations on cell surface EGFR expression and downstream signaling.
• Examined AGR2's role in EGFR-mediated signaling in tyrosine kinase inhibitor-resistant cells.

Main Results:

• AGR2 binding in the endoplasmic reticulum is crucial for EGFR delivery to the plasma membrane and subsequent signaling.
• Decreased AGR2 levels or activity lead to reduced cell surface EGFR and diminished signaling (AREG, EGR1, FOS expression).
• AGR2 deficiency causes embryonic lethality, similar to EGFR nulls, highlighting its fundamental role.
• AGR2 expression is elevated in many cancers, promoting a transformed phenotype and impacting EGFR signaling in resistant cell lines.

Conclusions:

• AGR2 acts as a novel post-translational regulator of EGFR signaling by controlling receptor cell surface delivery.
• AGR2 levels, not just EGFR protein or RNA, are critical for predicting cancer prognosis and therapeutic response.
• AGR2 represents a promising new therapeutic target for human cancers, particularly those involving EGFR.