Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling.
Ganlan BianCaiyong YuLing LiuChao FangKun ChenQian ZhangFangfang LiuKun ZhangQian XueJie XiangHongmin GuoJun SongYu ZhaoWutian WuSookja K ChungRuixia SunGong JuJian WangPublished in: Science signaling (2018)
In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. We identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one of several EGFR ligands rescued the EOB Spns2 mutant phenotype in vivo and in tissue explants in vitro and rescued the formation of stress fibers in primary keratinocytes from mutants. S1P signaled through the receptors S1PR1, S1PR2, and S1PR3 to activate extracellular signal-regulated kinase (ERK) and EGFR-dependent mitogen-activated protein kinase kinase kinase 1 (MEKK1)-c-Jun signaling. S1P also induced the nuclear translocation of the transcription factor MAL in a manner dependent on EGFR signaling. MAL and c-Jun stimulated the expression of the microRNAs miR-21 and miR-222, both of which target the metalloprotease inhibitor TIMP3, thus promoting metalloprotease activity. The metalloproteases ADAM10 and ADAM17 stimulated EGFR signaling by cleaving a membrane-anchored form of EGF to release the ligand. Our results outline a network by which S1P transactivates EGFR signaling through a complex mechanism involving feedback between several intra- and extracellular molecules to promote eyelid fusion in the developing rat.
Keyphrases
- epidermal growth factor receptor
- tyrosine kinase
- small cell lung cancer
- advanced non small cell lung cancer
- signaling pathway
- wild type
- transcription factor
- oxidative stress
- poor prognosis
- early life
- cell proliferation
- long non coding rna
- induced apoptosis
- pi k akt
- minimally invasive
- protein kinase
- binding protein
- optical coherence tomography
- long noncoding rna
- cell cycle arrest
- pregnant women
- drug induced
- endoplasmic reticulum stress
- heat stress
- stress induced