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

Rayego-Mateos, Sandra; Rodrigues-Diez, Raquel; Luis Morgado-Pascual, Jose; Rodrigues Diez, Raul R.; Mas, Sebastian; Lavoz, Carolina; Alique, Matilde; Pato, Janos; Keri, Gyorgy; Ortiz, Alberto; Egido, Jesus; Ruiz-Ortega, Marta

Abstract

Chronic kidney disease is reaching epidemic proportions worldwide and there is no effective treatment. Connective tissue growth factor (CCN2) has been suggested as a risk biomarker and a potential therapeutic target for renal diseases, but its specific receptor has not been identified. Epidermal growth factor receptor (EGFR) participates in kidney damage, but whether CCN2 activates the EGFR pathway is unknown. Here, we show that CCN2 is a novel EGFR ligand. CCN2 binding to EGFR extracellular domain was demonstrated by surface plasmon resonance. CCN2 contains four distinct structural modules. The carboxyl-terminal module (CCN2(IV)) showed a clear interaction with soluble EGFR, suggesting that EGFR-binding site is located in this module. Injection of CCN2(IV) in mice increased EGFR phosphorylation in the kidney, mainly in tubular epithelial cells. EGFR kinase inhibition decreased CCN2(IV)-induced renal changes (ERK activation and inflammation). Studies in cultured tubular epithelial cells showed that CCN2(IV) binds to EGFR leading to ERK activation and proinflammatory factors overexpression. CCN2 interacts with the neurotrophin receptor TrkA, and EGFR/TrkA receptor crosstalk was found in response to CCN2(IV) stimulation. Moreover, endogenous CCN2 blockade inhibited TGF--induced EGFR activation. These findings indicate that CCN2 is a novel EGFR ligand that contributes to renal damage through EGFR signalling.

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Título según WOS: ID WOS:000325491200005 Not found in local WOS DB
Título de la Revista: JOURNAL OF MOLECULAR CELL BIOLOGY
Volumen: 5
Número: 5
Editorial: OXFORD UNIV PRESS
Fecha de publicación: 2013
Página de inicio: 323
Página final: 335
DOI:

10.1093/jmcb/mjt030

Notas: ISI