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Zhenlian Wang, Chang Jin, Hongxia Li, Canxia Li, Qiang Hou, Lili Tu; GPR48-Induced Keratinocyte Proliferation and Migration Occurs through c-Src-Mediated EGFR Transactivation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2047.
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G protein-coupled receptor 48 (GPR48) is known to mediate keratinocyte proliferation and migration via the epidermal growth factor receptor (EGFR) during eyelid development. However, the mechanism by which GPR48 mediates the transactivation of EGFR remains an enigma. Here, we attempt to explore the signaling pathways that GPR48 affects using Gpr48-/- keratinocytes.
The molecular mechanism underlying GPR48-mediated eyelid closure was explored using Western blot analysis with various inhibitors that affect the EGFR pathway. In vitro BrdU and scratch assays were used to determine cell proliferation and motility.
Our initial investigation showed that EGFR phosphorylation in Gpr48-/- cells was similar to Gpr48+/+ keratinocytes treated with an inhibitor of the EGFR tyrosine kinase, AG1478. In addition, AG1478 could block GPR48-mediated cell proliferation and migration, thereby demonstrating the necessity of GPR48 in EGFR transactivation. AG1478 treatment on Gpr48+/+ cells also decreased phosphorylation of ERK and STAT3, both downstream targets of EGFR. Treatment with the toxin PP2, an inhibitor of c-Src, reduced GPR48-incuced c-Src phosphorylation and c-Src association with EGFR, and suppressed GPR48-induced phosphorylation of EGFR, ERK and STAT3.
We conclude that GPR48 mediates EGFR-induced cell proliferation and migration through c-Src.
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