Connective tissue growth factor is a new ligand of epidermal growth factor receptor.
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.
Cellular Biology in Renal Diseases Laboratory, Universidad Autónoma de Madrid, 28040 Madrid, Spain.
Sandra
S
Rayego-Mateos
Raquel
R
Rodrigues-Díez
Jose Luis
JL
Morgado-Pascual
Raul R
RR
Rodrigues Díez
Sebastian
S
Mas
Carolina
C
Lavoz
Matilde
M
Alique
Janos
J
Pato
Gyorgy
G
Keri
Alberto
A
Ortiz
Jesus
J
Egido
Marta
M
Ruiz-Ortega
D051722:ADAM Proteins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000737:chemistry / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D020239:Receptor Cross-Talk / Q000187:drug effects; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D016023:Integrins; D008024:Ligands; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D066246:ErbB Receptors; D020917:Receptor, trkA; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases
CCN2; EGFR; TrkA, renal; inflammation; receptors