GPR48-Induced keratinocyte proliferation occurs through HB-EGF mediated EGFR transactivation.
GPR48 can mediate keratinocyte proliferation and migration. Our investigations showed that AG1478, an inhibitor of EGFR tyrosine kinase, could block GPR48-mediated cellular processes. AG1478 treatment of Gpr48(+/+) cells also decreased phosphorylation of EGFR, ERK and STAT3. Subsequent screening using conditioned media immunodepleted of EGFR ligands identified HB-EGF as the ligand responsible for phosphorylation of EGFR, ERK and STAT3. HB-EGF was reduced in Gpr48(-/-) cell culture medium, but its addition restored the phosphorylation of EGFR, ERK, STAT3, as well as cell proliferation. Confirmation that GPR48 mediates EGFR signaling pathway through HB-EGF was subsequently performed using an inhibitor of HB-EGF.
Wang
Zhenlian
Z
School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China.
Jin
Chang
C
Li
Hongxia
H
Li
Canxia
C
Hou
Qiang
Q
Liu
Mingyao
M
Dong
Xiang Da Eric
Xda E
Tu
LiLi
L
D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics*; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation; D020032:Tyrphostins / Q000494:pharmacology
D001426:Bacterial Proteins; D017077:Culture Media, Conditioned; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C496200:LGR4 protein, mouse; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020032:Tyrphostins; C028581:CRM197 (non-toxic variant of diphtheria toxin); C101044:RTKI cpd; D066246:ErbB Receptors