Connective tissue growth factor is a new ligand of epidermal growth factor receptor

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Chronic kidney disease (CKD) is a global health crisis with limited treatment options.
• Connective tissue growth factor (CCN2) is implicated in renal diseases, but its receptor and signaling pathways remain unclear.
• Epidermal growth factor receptor (EGFR) is involved in kidney injury, but its connection to CCN2 is unknown.

Purpose of the Study:

• To identify the specific receptor for CCN2 in the context of renal disease.
• To investigate whether CCN2 activates the EGFR pathway.
• To elucidate the role of CCN2-EGFR interaction in kidney damage.

Main Methods:

• Surface plasmon resonance to demonstrate CCN2 binding to EGFR.
• In vivo studies using mice injected with CCN2 carboxyl-terminal module (CCN2(IV)).
• In vitro studies using cultured tubular epithelial cells and EGFR kinase inhibitors.

Main Results:

• CCN2 directly binds to the extracellular domain of EGFR, with the carboxyl-terminal module (CCN2(IV)) being the primary binding site.
• CCN2(IV) injection induced EGFR phosphorylation, ERK activation, and inflammation in mouse kidneys.
• EGFR inhibition attenuated CCN2(IV)-induced renal damage.
• CCN2(IV) activated ERK and proinflammatory factors in tubular cells via EGFR.
• CCN2 also interacts with TrkA, and EGFR/TrkA crosstalk was observed.
• Blocking CCN2 inhibited TGF-β-induced EGFR activation.

Conclusions:

• CCN2 is identified as a novel ligand for EGFR.
• CCN2-mediated EGFR activation contributes to renal damage through downstream signaling.
• Targeting the CCN2-EGFR interaction presents a potential therapeutic strategy for kidney diseases.