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

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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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-β-induced EGFR activation. These findings indicate that CCN2 is a novel EGFR ligand that contributes to renal damage through EGFR signalling.

Original languageEnglish
Pages (from-to)323-335
Number of pages13
JournalJournal of Molecular Cell Biology
Volume5
Issue number5
DOIs
Publication statusPublished - Oct 2013

Fingerprint

Connective Tissue Growth Factor
Epidermal Growth Factor Receptor
Ligands
Kidney
trkA Receptor
Epithelial Cells
Nerve Growth Factor Receptors
Surface Plasmon Resonance
Chronic Renal Insufficiency

Keywords

  • CCN2
  • EGFR
  • inflammation
  • receptors
  • TrkA, renal

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Genetics

Cite this

Rayego-Mateos, S., Rodrigues-Díez, R., Morgado-Pascual, J. L., Rodrigues Díez, R. R., Mas, S., Lavoz, C., ... Ruiz-Ortega, M. (2013). Connective tissue growth factor is a new ligand of epidermal growth factor receptor. Journal of Molecular Cell Biology, 5(5), 323-335. https://doi.org/10.1093/jmcb/mjt030

Connective tissue growth factor is a new ligand of epidermal growth factor receptor. / Rayego-Mateos, Sandra; Rodrigues-Díez, Raquel; Morgado-Pascual, Jose Luis; Rodrigues Díez, Raul R.; Mas, Sebastian; Lavoz, Carolina; Alique, Matilde; Pato, Janos; Kéri, G.; Ortiz, Alberto; Egido, Jesus; Ruiz-Ortega, Marta.

In: Journal of Molecular Cell Biology, Vol. 5, No. 5, 10.2013, p. 323-335.

Research output: Contribution to journalArticle

Rayego-Mateos, S, Rodrigues-Díez, R, Morgado-Pascual, JL, Rodrigues Díez, RR, Mas, S, Lavoz, C, Alique, M, Pato, J, Kéri, G, Ortiz, A, Egido, J & Ruiz-Ortega, M 2013, 'Connective tissue growth factor is a new ligand of epidermal growth factor receptor', Journal of Molecular Cell Biology, vol. 5, no. 5, pp. 323-335. https://doi.org/10.1093/jmcb/mjt030
Rayego-Mateos S, Rodrigues-Díez R, Morgado-Pascual JL, Rodrigues Díez RR, Mas S, Lavoz C et al. Connective tissue growth factor is a new ligand of epidermal growth factor receptor. Journal of Molecular Cell Biology. 2013 Oct;5(5):323-335. https://doi.org/10.1093/jmcb/mjt030
Rayego-Mateos, Sandra ; Rodrigues-Díez, Raquel ; Morgado-Pascual, Jose Luis ; Rodrigues Díez, Raul R. ; Mas, Sebastian ; Lavoz, Carolina ; Alique, Matilde ; Pato, Janos ; Kéri, G. ; Ortiz, Alberto ; Egido, Jesus ; Ruiz-Ortega, Marta. / Connective tissue growth factor is a new ligand of epidermal growth factor receptor. In: Journal of Molecular Cell Biology. 2013 ; Vol. 5, No. 5. pp. 323-335.
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