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

Chronickidneydiseaseisreachingepidemicproportionsworldwideandthereisnoeffectivetreatment.Connectivetissuegrowthfactor(CCN2)hasbeensuggestedasariskbiomarkerandapotentialtherapeutictargetforrenaldiseases,butitsspecificreceptorhasnotbeenidentified.Epidermalgrowthfactorreceptor(EGFR)participatesinkidneydamage,butwhetherCCN2activatestheEGFRpathwayisunknown.Here,weshowthatCCN2isanovelEGFRligand.CCN2bindingtoEGFRextracellulardomainwasdemonstratedbysurfaceplasmon resonance. CCN2 contains four distinct structural modules. The carboxyl-terminal module (CCN2(IV)) showed a clear inter-action with soluble EGFR, suggesting that EGFR-binding site is located in this module. Injection of CCN2(IV) in mice increased EGFRphosphorylation in the kidney, mainly in tubular epithelial cells. EGFR kinase inhibition decreased CCN2(IV)-induced renal changes(ERKactivationandinflammation).StudiesinculturedtubularepithelialcellsshowedthatCCN2(IV)bindstoEGFRleadingtoERKac-tivation and proinflammatory factors overexpression. CCN2 interacts with the neurotrophin receptor TrkA, and EGFR/TrkA receptorcrosstalk was found in response to CCN2(IV) stimulation. Moreover, endogenous CCN2 blockade inhibited TGF-b-induced EGFR acti-vation. These findings indicatethatCCN2 is a novelEGFR ligand thatcontributesto renal damage through EGFR signalling.